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Maritan, Martina (2017) Structural characterization of the human immune response to the meningococcal vaccine antigen NHBA. [Ph.D. thesis]

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Abstract (english)

Neisseria meningitidis is a human pathogen which can cause fatal sepsis and invasive meningococcal disease once it reaches the blood stream and the nervous system. Bexsero™ is the first broadly protective multicomponent vaccine against serogroup B N. meningitidis. Among itscomponents, the Neisserial Heparin Binding Antigen (NHBA) represents the less structurally and functionally characterized antigen of Bexsero and therefore has been the target of the current study.NHBA is a surface-exposed lipoprotein composed by two domains (C- and N-terminal), and while the structure of the C-terminal domain was solved by NMR, the structure of N-terminal region is still unknown and predicted to be largely unstructured. Knowledge of the NHBA full-length structure canprovide important insights towards the understanding of its biological function, as well as on its role as vaccine antigen.In this work we combined the information derived from the profiling the B-cell repertoire in response to vaccination with Bexsero with structural biology, in order to shed light on NHBA structure and on the molecular bases of its recognition by the human immune system. By using fragments antigen binding (Fabs) derived from human monoclonal antibodies (mAbs), we sought to provide highresolution epitope mapping of the NHBA immunogenic regions, which in turn could permit a deeper characterization of the molecular determinants of antibody binding and protective epitopes. Here we present a structural characterization of the first high-resolution crystal structures of three free human anti-NHBA Fabs of NHBA. These structures reveal features compatible with the binding of NHBA regions as previously determined by other low-resolution methods. Moreover, these Fabs provided important tools for structural studies through co-crystallization experiments with various NHBA fragments and constructs. While using Fabs that bind to the NHBA N-terminal region complexed with full length or sub-full length antigen did not result in crystal growth, a construct including solely the C-terminal domain yielded crystals that allowed solving the structure of the complex with a C-terminal Fab binder. Structural analysis highlighted the conservation of the epitope and lead to the identification of the key residues involved into NHBA-Fab recognition. Additionally, the comparison between bound and unbound Fab revealed an interesting fitting mechanism occurring during antigen recognition that provides further details into the elucidation of antibody binding. Combined together, these results enhance our structural and biophysical understanding of NHBA, and provide a platform for deeper analyses aimed at the elucidation of the molecular determinants of its immunogenicity.

Abstract (italian)

Neisseria meningitidis è un patogeno umano obbligato e un potenziale agente eziologico di sepsi e meningite, qualora entri in contatto con il flusso sanguigno o il sistema nervoso. Bexsero è il primo vaccino multicomponente in grado di fornire ampia protezione contro il sierogruppo B di N meningitidis. Tra i vari componenti di Bexsero, Neisserial Heparin Binding Antigen (NHBA) rappresenta l’antigene meno caratterizzato sia funzionalmente che strutturalmente e, per questa ragione, è stato selezionato come oggetto di studio nel presente lavoro. NHBA è una lipoproteina esposta sulla superficie del batterio e si compone di due domini (C- e N-terminale); mentre la struttura del dominio C-terminale è stata risolta tramite spettroscopia NMR, il dominio N-terminale è ancora strutturalmente non caratterizzato e predetto, per la maggior parte della sua sequenza, come non strutturato. La conoscenza delle caratteristiche strutturali della proteina intera, quindi, potrebbe essere utile per chiarire il ruolo che NHBA svolge sia dal punto di vista biologico sia come antigene vaccinale. In questo lavoro di tesi, informazioni derivanti dall’analisi del repertorio delle cellule B generate in risposta all’immunizzazione con Bexsero sono state combinante con tecniche di biologia strutturale (cristallografia a raggi X), in modo da delucidare la struttura completa di NHBA e le basi molecolari del suo riconoscimento da parte del sistema immunitario umano. Frammenti di anticorpi leganti l'antigene (Fabs), derivanti da anticorpi monoclonali umani (mAbs) sono stati utilizzati per la mappatura ad altarisoluzione degli epitopi immunogenici di NHBA, permettendo un’accurata caratterizzazione dal punto di vista molecolare delle regioni dell’antigene implicate nel legame con gli anticorpi. Dall’analisi delle strutture cristallografiche ad alta risoluzione di tre Fabs umani diretti controNHBA, è emerso che questi presentano a livello del paratopo caratteristiche che indicano la loro compatibilità con il legame a NHBA tramite regioni precedente mappate con tecniche a bassa risoluzione. Inoltre, questi Fabs si sono rivelati un importante strumento per studi strutturali attraverso esperimenti di co-cristallizzazione in complesso con NHBA. Purtroppo non è stato possibile ottenere cristalli idonei per esperimenti di diffrazione dalla co-cristallizzazione dei Fabs con l’intera NHBA o frammenti N-terminali di NHBA; al contrario, il dominio C-terminale dell’antigene in complesso con un Fab ha generato cristalli che hanno permesso di risolvere la prima struttura di un complesso tra Cterminale di NHBA e un Fab umano. L’analisi strutturale di questo complesso ha evidenziato l’estrema conservazione dell’epitopo e guidato l’identificazione dei residui chiave implicati nel riconoscimento tra NHBA e Fab. Inoltre, il confronto tra la forma complessata e non-complessata del Fab ha rivelato un 8 interessante meccanismo di legame che avviene nella fase di riconoscimento dell’antigene e che fornisce ulteriori dettagli sui meccanismi che regolano i legami tra anticorpi e antigeni. I risultati ottenuti in questo studio hanno contribuito a migliorare la conoscenza strutturale e biofisica di NHBA e forniscono una base per una futura analisi strutturale più accurata, volta a delucidare i dettagli molecolari della risposta immunitaria a NHBA.

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EPrint type:Ph.D. thesis
Tutor:Montecucco, Cesare
Supervisor:Malito, Enrico
Ph.D. course:Ciclo 29 > Corsi 29 > BIOSCIENZE E BIOTECNOLOGIE
Data di deposito della tesi:10 April 2017
Anno di Pubblicazione:17 March 2017
Key Words:NHBA, vaccine, crystallography, antibodies
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:10407
Depositato il:14 Nov 2017 15:09
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I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

1. Delany, I., R. Rappuoli, and E. De Gregorio, Vaccines for the 21st century. EMBO Molecular Medicine, Cerca con Google

2014. 6(6): p. 708-720. Cerca con Google

2. WHO. Global VaccineActionPlan2011–2020. 2013. Cerca con Google

3. De Gregorio, E. and R. Rappuoli, From empiricism to rational design: a personal perspective of the Cerca con Google

evolution of vaccine development. Nat Rev Immunol, 2014. 14(7): p. 505-14. Cerca con Google

4. Plotkin, S., History of vaccination. Proc Natl Acad Sci U S A, 2014. 111(34): p. 12283-7. Cerca con Google

5. Rappuoli, R., Vaccines: Science, health, longevity, and wealth. Proceedings of the National Academy of Cerca con Google

Sciences of the United States of America, 2014. 111(34): p. 12282-12282. Cerca con Google

6. Rappuoli, R., Reverse vaccinology, a genome-based approach to vaccine development. Vaccine, 2001. Cerca con Google

19(17-19): p. 2688-91. Cerca con Google

7. Rappuoli, R., Reverse vaccinology. Curr Opin Microbiol, 2000. 3(5): p. 445-50. Cerca con Google

8. Tettelin, H., et al., Complete genome sequence of Neisseria meningitidis serogroup B strain MC58. Cerca con Google

Science, 2000. 287(5459): p. 1809-15. Cerca con Google

9. Rinaudo, C.D., et al., Vaccinology in the genome era. The Journal of Clinical Investigation, 2009. 119(9): Cerca con Google

p. 2515-2525. Cerca con Google

10. Liljeroos Lassi, E.M., Ilaria Ferlenghi and Matthew James Bottomley, Structural and computational Cerca con Google

biology in the design of immunogenic vaccine antigens. 2015. Cerca con Google

11. Vytvytska, O., et al., Identification of vaccine candidate antigens of Staphylococcus aureus by Cerca con Google

serological proteome analysis. Proteomics, 2002. 2(5): p. 580-90. Cerca con Google

12. Couto, N., et al., Identification of vaccine candidate antigens of Staphylococcus pseudintermedius by Cerca con Google

whole proteome characterization and serological proteomic analyses. J Proteomics, 2016. 133: p. 113- Cerca con Google

24. Cerca con Google

13. Serruto, D., et al., The new multicomponent vaccine against meningococcal serogroup B, 4CMenB: Cerca con Google

immunological, functional and structural characterization of the antigens. Vaccine, 2012. 30 Suppl 2: p. Cerca con Google

B87-97. Cerca con Google

14. Donnarumma, D., et al., The role of structural proteomics in vaccine development: recent advances and Cerca con Google

future prospects. Expert Review of Proteomics, 2016. 13(1): p. 55-68. Cerca con Google

15. Chiang, M.H., et al., Identification of novel vaccine candidates against Acinetobacter baumannii using Cerca con Google

reverse vaccinology. Hum Vaccin Immunother, 2015. 11(4): p. 1065-73. Cerca con Google

16. Montigiani, S., et al., Genomic approach for analysis of surface proteins in Chlamydia pneumoniae. Cerca con Google

Infect Immun, 2002. 70(1): p. 368-79. Cerca con Google

17. Naz, A., et al., Identification of putative vaccine candidates against Helicobacter pylori exploiting Cerca con Google

exoproteome and secretome: a reverse vaccinology based approach. Infect Genet Evol, 2015. 32: p. Cerca con Google

280-91. Cerca con Google

18. Talukdar, S., et al., Identification of potential vaccine candidates against Streptococcus pneumoniae by Cerca con Google

reverse vaccinology approach. Appl Biochem Biotechnol, 2014. 172(6): p. 3026-41. Cerca con Google

19. Xiang, Z. and Y. He, Genome-wide prediction of vaccine targets for human herpes simplex viruses using Cerca con Google

Vaxign reverse vaccinology. BMC Bioinformatics, 2013. 14 Suppl 4: p. S2. Cerca con Google

20. Rappuoli, R., et al., Reverse vaccinology 2.0: Human immunology instructs vaccine antigen design. The Cerca con Google

Journal of Experimental Medicine, 2016. 213(4): p. 469-481. Cerca con Google

21. Lanzavecchia, A., et al., Antibody-guided vaccine design: identification of protective epitopes. Curr Opin Cerca con Google

Immunol, 2016. 41: p. 62-7. Cerca con Google

22. McLellan, J.S., et al., Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial Cerca con Google

virus. Science, 2013. 342(6158): p. 592-8. Cerca con Google

82 Cerca con Google

23. Kwon, Y.D., et al., Crystal structure, conformational fixation and entry-related interactions of mature Cerca con Google

ligand-free HIV-1 Env. Nat Struct Mol Biol, 2015. 22(7): p. 522-31. Cerca con Google

24. Scarselli, M., et al., Rational design of a meningococcal antigen inducing broad protective immunity. Sci Cerca con Google

Transl Med, 2011. 3(91): p. 91ra62. Cerca con Google

25. Nuccitelli, A., et al., Structure-based approach to rationally design a chimeric protein for an effective Cerca con Google

vaccine against Group B Streptococcus infections. Proc Natl Acad Sci U S A, 2011. 108(25): p. 10278-83. Cerca con Google

26. Dormitzer, P.R., J.B. Ulmer, and R. Rappuoli, Structure-based antigen design: a strategy for next Cerca con Google

generation vaccines. Trends Biotechnol, 2008. 26(12): p. 659-67. Cerca con Google

27. Malito, E., A. Carfi, and M.J. Bottomley, Protein Crystallography in Vaccine Research and Development. Cerca con Google

Int J Mol Sci, 2015. 16(6): p. 13106-40. Cerca con Google

28. Malito, E., et al., Defining a protective epitope on factor H binding protein, a key meningococcal Cerca con Google

virulence factor and vaccine antigen. Proceedings of the National Academy of Sciences of the United Cerca con Google

States of America, 2013. 110(9): p. 3304-3309. Cerca con Google

29. Malito, E., et al., Structure of the meningococcal vaccine antigen NadA and epitope mapping of a Cerca con Google

bactericidal antibody. Proc Natl Acad Sci U S A, 2014. 111(48): p. 17128-33. Cerca con Google

30. Godley, L., et al., Introduction of intersubunit disulfide bonds in the membrane-distal region of the Cerca con Google

influenza hemagglutinin abolishes membrane fusion activity. Cell, 1992. 68(4): p. 635-45. Cerca con Google

31. Lee, J.K., et al., Reversible Inhibition of the Fusion Activity of Measles Virus F Protein by an Engineered Cerca con Google

Intersubunit Disulfide Bridge. Journal of Virology, 2007. 81(16): p. 8821-8826. Cerca con Google

32. McNeil, G., M. Virji, and E.R. Moxon, Interactions of Neisseria meningitidis with human monocytes. Cerca con Google

Microb Pathog, 1994. 16(2): p. 153-63. Cerca con Google

33. Harrison, O.B., et al., Description and Nomenclature of Neisseria meningitidis Capsule Locus. Emerging Cerca con Google

Infectious Diseases, 2013. 19(4): p. 566-573. Cerca con Google

34. Branham, S.E., SEROLOGICAL RELATIONSHIPS AMONG MENINGOCOCCI. Bacteriological Reviews, 1953. Cerca con Google

17(3): p. 175-188. Cerca con Google

35. Rouphael, N.G. and D.S. Stephens, Neisseria meningitidis: biology, microbiology, and epidemiology. Cerca con Google

Methods Mol Biol, 2012. 799: p. 1-20. Cerca con Google

36. Rosenstein, N.E., et al., Meningococcal disease. N Engl J Med, 2001. 344(18): p. 1378-88. Cerca con Google

37. Stephens, D.S., B. Greenwood, and P. Brandtzaeg, Epidemic meningitis, meningococcaemia, and Cerca con Google

Neisseria meningitidis. Lancet, 2007. 369(9580): p. 2196-210. Cerca con Google

38. Caugant, D.A. and M.C. Maiden, Meningococcal carriage and disease--population biology and Cerca con Google

evolution. Vaccine, 2009. 27 Suppl 2: p. B64-70. Cerca con Google

39. Brooks, R., et al., Increased case-fatality rate associated with outbreaks of Neisseria meningitidis Cerca con Google

infection, compared with sporadic meningococcal disease, in the United States, 1994-2002. Clin Infect Cerca con Google

Dis, 2006. 43(1): p. 49-54. Cerca con Google

40. Virji, M., Pathogenic neisseriae: surface modulation, pathogenesis and infection control. Nat Rev Cerca con Google

Microbiol, 2009. 7(4): p. 274-86. Cerca con Google

41. Pizza, M. and R. Rappuoli, Neisseria meningitidis: pathogenesis and immunity. Curr Opin Microbiol, Cerca con Google

2015. 23: p. 68-72. Cerca con Google

42. van Deuren, M., P. Brandtzaeg, and J.W. van der Meer, Update on meningococcal disease with Cerca con Google

emphasis on pathogenesis and clinical management. Clin Microbiol Rev, 2000. 13(1): p. 144-66, table of Cerca con Google

contents. Cerca con Google

43. Khatami, A. and A.J. Pollard, The epidemiology of meningococcal disease and the impact of vaccines. Cerca con Google

Expert Rev Vaccines, 2010. 9(3): p. 285-98. Cerca con Google

44. Lewis, L.A. and S. Ram, Meningococcal disease and the complement system. Virulence, 2014. 5(1): p. Cerca con Google

98-126. Cerca con Google

83 Cerca con Google

45. Scholten, R.J., et al., Meningococcal disease in The Netherlands, 1958-1990: a steady increase in the Cerca con Google

incidence since 1982 partially caused by new serotypes and subtypes of Neisseria meningitidis. Clin Cerca con Google

Infect Dis, 1993. 16(2): p. 237-46. Cerca con Google

46. Finne, J., M. Leinonen, and P.H. Makela, Antigenic similarities between brain components and bacteria Cerca con Google

causing meningitis. Implications for vaccine development and pathogenesis. Lancet, 1983. 2(8346): p. Cerca con Google

355-7. Cerca con Google

47. Finne, J., et al., An IgG monoclonal antibody to group B meningococci cross-reacts with developmentally Cerca con Google

regulated polysialic acid units of glycoproteins in neural and extraneural tissues. J Immunol, 1987. Cerca con Google

138(12): p. 4402-7. Cerca con Google

48. Giuliani, M.M., et al., A universal vaccine for serogroup B meningococcus. Proc Natl Acad Sci U S A, Cerca con Google

2006. 103(29): p. 10834-9. Cerca con Google

49. Pizza, M., et al., Identification of vaccine candidates against serogroup B meningococcus by wholegenome Cerca con Google

sequencing. Science, 2000. 287(5459): p. 1816-20. Cerca con Google

50. Welsch, J.A., et al., Antibody to genome-derived neisserial antigen 2132, a Neisseria meningitidis Cerca con Google

candidate vaccine, confers protection against bacteremia in the absence of complement-mediated Cerca con Google

bactericidal activity. J Infect Dis, 2003. 188(11): p. 1730-40. Cerca con Google

51. McQuaid, F., et al., Persistence of bactericidal antibodies to 5 years of age after immunization with Cerca con Google

serogroup B meningococcal vaccines at 6, 8, 12 and 40 months of age. Pediatr Infect Dis J, 2014. 33(7): Cerca con Google

p. 760-6. Cerca con Google

52. Prymula, R., et al., A phase 2 randomized controlled trial of a multicomponent meningococcal Cerca con Google

serogroup B vaccine (I). Hum Vaccin Immunother, 2014. 10(7): p. 1993-2004. Cerca con Google

53. Fletcher, L.D., et al., Vaccine potential of the Neisseria meningitidis 2086 lipoprotein. Infect Immun, Cerca con Google

2004. 72(4): p. 2088-100. Cerca con Google

54. Jiang, H.Q., et al., Broad vaccine coverage predicted for a bivalent recombinant factor H binding protein Cerca con Google

based vaccine to prevent serogroup B meningococcal disease. Vaccine, 2010. 28(37): p. 6086-93. Cerca con Google

55. Richmond, P.C., et al., Safety, immunogenicity, and tolerability of meningococcal serogroup B bivalent Cerca con Google

recombinant lipoprotein 2086 vaccine in healthy adolescents: a randomised, single-blind, placebocontrolled, Cerca con Google

phase 2 trial. Lancet Infect Dis, 2012. 12(8): p. 597-607. Cerca con Google

56. Serruto, D., et al., Neisseria meningitidis GNA2132, a heparin-binding protein that induces protective Cerca con Google

immunity in humans. Proc Natl Acad Sci U S A, 2010. 107(8): p. 3770-5. Cerca con Google

57. Giuliani, M.M., et al., Measuring antigen-specific bactericidal responses to a multicomponent vaccine Cerca con Google

against serogroup B meningococcus. Vaccine, 2010. 28(31): p. 5023-30. Cerca con Google

58. Bambini, S., et al., Distribution and genetic variability of three vaccine components in a panel of strains Cerca con Google

representative of the diversity of serogroup B meningococcus. Vaccine, 2009. 27(21): p. 2794-803. Cerca con Google

59. Jacobsson, S., et al., Sequence constancies and variations in genes encoding three new meningococcal Cerca con Google

vaccine candidate antigens. Vaccine, 2006. 24(12): p. 2161-8. Cerca con Google

60. Lucidarme, J., et al., Characterization of fHbp, nhba (gna2132), nadA, porA, and sequence type in group Cerca con Google

B meningococcal case isolates collected in England and Wales during January 2008 and potential Cerca con Google

coverage of an investigational group B meningococcal vaccine. Clin Vaccine Immunol, 2010. 17(6): p. Cerca con Google

919-29. Cerca con Google

61. Muzzi, A., et al., Conservation of meningococcal antigens in the genus Neisseria. MBio, 2013. 4(3): p. Cerca con Google

e00163-13. Cerca con Google

62. Bambini, S., et al., An analysis of the sequence variability of meningococcal fHbp, NadA and NHBA over Cerca con Google

a 50-year period in the Netherlands. PLoS One, 2013. 8(5): p. e65043. Cerca con Google

63. Vogel, U., et al., Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Cerca con Google

Europe: a qualitative and quantitative assessment. Lancet Infect Dis, 2013. 13(5): p. 416-25. Cerca con Google

84 Cerca con Google

64. Esposito, V., et al., Structure of the C-terminal domain of Neisseria heparin binding antigen (NHBA), one Cerca con Google

of the main antigens of a novel vaccine against Neisseria meningitidis. J Biol Chem, 2011. 286(48): p. Cerca con Google

41767-75. Cerca con Google

65. Flower, D.R., A.C. North, and C.E. Sansom, The lipocalin protein family: structural and sequence Cerca con Google

overview. Biochim Biophys Acta, 2000. 1482(1-2): p. 9-24. Cerca con Google

66. Calmettes, C., et al., Structural variations within the transferrin binding site on transferrin-binding Cerca con Google

protein B, TbpB. J Biol Chem, 2011. 286(14): p. 12683-92. Cerca con Google

67. Casellato, A., et al., The C2 fragment from Neisseria meningitidis antigen NHBA increases endothelial Cerca con Google

permeability by destabilizing adherens junctions. Cell Microbiol, 2014. 16(6): p. 925-37. Cerca con Google

68. Lehninger, Principles of Biochemistry. 5 ed. 2008. Cerca con Google

69. Janeway CA Jr, T.P., Walport M, et al., Immunobiology: The Immune System in Health and Disease. 5 ed. Cerca con Google

2001: Garland Science. Cerca con Google

70. Halaby, D.M., A. Poupon, and J. Mornon, The immunoglobulin fold family: sequence analysis and 3D Cerca con Google

structure comparisons. Protein Eng, 1999. 12(7): p. 563-71. Cerca con Google

71. Stanfield, R.L. and I.A. Wilson, Antibody Structure. Microbiol Spectr, 2014. 2(2). Cerca con Google

72. Davies, D.R. and G.H. Cohen, Interactions of protein antigens with antibodies. Proc Natl Acad Sci U S A, Cerca con Google

1996. 93(1): p. 7-12. Cerca con Google

73. Davies, D.R., E.A. Padlan, and D.M. Segal, Three-dimensional structure of immunoglobulins. Annu Rev Cerca con Google

Biochem, 1975. 44: p. 639-67. Cerca con Google

74. Sela-Culang, I., V. Kunik, and Y. Ofran, The Structural Basis of Antibody-Antigen Recognition. Front Cerca con Google

Immunol, 2013. 4. Cerca con Google

75. Yu, C.M., et al., Rationalization and design of the complementarity determining region sequences in an Cerca con Google

antibody-antigen recognition interface. PLoS One, 2012. 7(3): p. e33340. Cerca con Google

76. Chothia, C. and A.M. Lesk, Canonical structures for the hypervariable regions of immunoglobulins. J Mol Cerca con Google

Biol, 1987. 196(4): p. 901-17. Cerca con Google

77. Martin, A.C. and J.M. Thornton, Structural families in loops of homologous proteins: automatic Cerca con Google

classification, modelling and application to antibodies. J Mol Biol, 1996. 263(5): p. 800-15. Cerca con Google

78. Al-Lazikani, B., A.M. Lesk, and C. Chothia, Standard conformations for the canonical structures of Cerca con Google

immunoglobulins1. Journal of Molecular Biology, 1997. 273(4): p. 927-948. Cerca con Google

79. North, B., A. Lehmann, and R.L. Dunbrack, Jr., A new clustering of antibody CDR loop conformations. J Cerca con Google

Mol Biol, 2011. 406(2): p. 228-56. Cerca con Google

80. Abbott, W.M., M.M. Damschroder, and D.C. Lowe, Current approaches to fine mapping of antigenantibody Cerca con Google

interactions. Immunology, 2014. 142(4): p. 526-35. Cerca con Google

81. Wilson, P.C. and S.F. Andrews, Tools to therapeutically harness the human antibody response. Nat Rev Cerca con Google

Immunol, 2012. 12(10): p. 709-19. Cerca con Google

82. Back, J.W. and J.P. Langedijk, Structure-based design for high-hanging vaccine fruits. Adv Immunol, Cerca con Google

2012. 114: p. 33-50. Cerca con Google

83. Gershoni, J.M., et al., Epitope mapping: the first step in developing epitope-based vaccines. BioDrugs, Cerca con Google

2007. 21(3): p. 145-56. Cerca con Google

84. Ladner, R.C., Mapping the Epitopes of Antibodies. Biotechnology and Genetic Engineering Reviews, Cerca con Google

2007. 24(1): p. 1-30. Cerca con Google

85. Hudson, E.P., M. Uhlen, and J. Rockberg, Multiplex epitope mapping using bacterial surface display Cerca con Google

reveals both linear and conformational epitopes. Sci Rep, 2012. 2: p. 706. Cerca con Google

86. Barlow, D.J., M.S. Edwards, and J.M. Thornton, Continuous and discontinuous protein antigenic Cerca con Google

determinants. Nature, 1986. 322(6081): p. 747-748. Cerca con Google

87. Van Regenmortel, M.H.V., Mapping Epitope Structure and Activity: From One-Dimensional Prediction to Cerca con Google

Four-Dimensional Description of Antigenic Specificity. Methods, 1996. 9(3): p. 465-72. Cerca con Google

85 Cerca con Google

88. Scietti, L., et al., Exploring host-pathogen interactions through genome wide protein microarray Cerca con Google

analysis. Sci Rep, 2016. 6: p. 27996. Cerca con Google

89. Griffin, L. and A. Lawson, Antibody fragments as tools in crystallography. Clin Exp Immunol, 2011. Cerca con Google

165(3): p. 285-91. Cerca con Google

90. Masignani, V., Characterization of the human antibody repertoire to type B meningococcal vaccine. Cerca con Google

19th International Pathogenic Neisseria Conference 2014. Poster #35 Cerca con Google

91. Giuliani, M., Characterization of the human antibody repertoire to type B meningococcus vaccine. 12th Cerca con Google

Congress of The European Meningococcal and Haemophilus Disease Society, 2015. Poster #43. Cerca con Google

92. Kelley, L.A., et al., The Phyre2 web portal for protein modeling, prediction and analysis. Nat. Protocols, Cerca con Google

2015. 10(6): p. 845-858. Cerca con Google

93. Kelley, L.A. and M.J. Sternberg, Protein structure prediction on the Web: a case study using the Phyre Cerca con Google

server. Nat Protoc, 2009. 4(3): p. 363-71. Cerca con Google

94. Adamczak, R., A. Porollo, and J. Meller, Combining prediction of secondary structure and solvent Cerca con Google

accessibility in proteins. Proteins, 2005. 59(3): p. 467-75. Cerca con Google

95. Buchan, D.W.A., et al., Scalable web services for the PSIPRED Protein Analysis Workbench. Nucleic Acids Cerca con Google

Research, 2013. 41(Web Server issue): p. W349-W357. Cerca con Google

96. Drozdetskiy, A., et al., JPred4: a protein secondary structure prediction server. Nucleic Acids Res, 2015. Cerca con Google

43(W1): p. W389-94. Cerca con Google

97. Cilia, E., et al., The DynaMine webserver: predicting protein dynamics from sequence. Nucleic Acids Cerca con Google

Research, 2014. 42(Web Server issue): p. W264-W270. Cerca con Google

98. Dosztanyi, Z., et al., IUPred: web server for the prediction of intrinsically unstructured regions of Cerca con Google

proteins based on estimated energy content. Bioinformatics, 2005. 21(16): p. 3433-4. Cerca con Google

99. Lieutaud, P., B. Canard, and S. Longhi, MeDor: a metaserver for predicting protein disorder. BMC Cerca con Google

Genomics, 2008. 9 Suppl 2: p. S25. Cerca con Google

100. Studier, F.W. and B.A. Moffatt, Use of bacteriophage T7 RNA polymerase to direct selective high-level Cerca con Google

expression of cloned genes. J Mol Biol, 1986. 189(1): p. 113-30. Cerca con Google

101. van den Berg, S., et al., Improved solubility of TEV protease by directed evolution. J Biotechnol, 2006. Cerca con Google

121(3): p. 291-8. Cerca con Google

102. Karlsson, R., et al., Analyzing a kinetic titration series using affinity biosensors. Anal Biochem, 2006. Cerca con Google

349(1): p. 136-47. Cerca con Google

103. Tong, Y., et al., Salvage or recovery of failed targets by in situ proteolysis. Methods Mol Biol, 2014. Cerca con Google

1140: p. 179-88. Cerca con Google

104. Dong, A., et al., In situ proteolysis for protein crystallization and structure determination. Nat Methods, Cerca con Google

2007. 4(12): p. 1019-21. Cerca con Google

105. Kabsch, W., XDS. Acta Crystallogr D Biol Crystallogr, 2010. 66(Pt 2): p. 125-32. Cerca con Google

106. Winn, M.D., et al., Overview of the CCP4 suite and current developments. Acta Crystallogr D Biol Cerca con Google

Crystallogr, 2011. 67(Pt 4): p. 235-42. Cerca con Google

107. Emsley, P., et al., Features and development of Coot. Acta Crystallogr D Biol Crystallogr, 2010. 66(Pt 4): Cerca con Google

p. 486-501. Cerca con Google

108. Adams, P.D., et al., PHENIX: a comprehensive Python-based system for macromolecular structure Cerca con Google

solution. Acta Crystallogr D Biol Crystallogr, 2010. 66(Pt 2): p. 213-21. Cerca con Google

109. Bricogne, G., et al., BUSTER version 2.11.4. Cambridge, United Kingdom: Global Phasing Ltd, 2016. Cerca con Google

110. Matthews, B.W., Solvent content of protein crystals. J Mol Biol, 1968. 33(2): p. 491-7. Cerca con Google

111. Vagin, A. and A. Lebedev, MoRDa, an automatic molecular replacement pipeline. Acta Crystallographica Cerca con Google

Section A, 2015. 71(a1): p. s19. Cerca con Google

112. McCoy, A.J., et al., Phaser crystallographic software. Journal of Applied Crystallography, 2007. 40(Pt 4): Cerca con Google

p. 658-674. Cerca con Google

86 Cerca con Google

113. Rould, M.A. and C.W. Carter, Jr., Isomorphous difference methods. Methods Enzymol, 2003. 374: p. Cerca con Google

145-63. Cerca con Google

114. Incardona, M.-F., et al., EDNA: a framework for plugin-based applications applied to X-ray experiment Cerca con Google

online data analysis. Journal of Synchrotron Radiation, 2009. 16(6): p. 872-879. Cerca con Google

115. Battye, T.G., et al., iMOSFLM: a new graphical interface for diffraction-image processing with MOSFLM. Cerca con Google

Acta Crystallogr D Biol Crystallogr, 2011. 67(Pt 4): p. 271-81. Cerca con Google

116. Zwart, P.H., et al., Automated structure solution with the PHENIX suite. Methods Mol Biol, 2008. 426: p. Cerca con Google

419-35. Cerca con Google

117. Teplyakov, A., et al., Antibody modeling assessment II. Structures and models. Proteins, 2014. 82(8): p. Cerca con Google

1563-82. Cerca con Google

118. Chen, V.B., et al., MolProbity: all-atom structure validation for macromolecular crystallography. Acta Cerca con Google

Crystallogr D Biol Crystallogr, 2010. 66(Pt 1): p. 12-21. Cerca con Google

119. Krissinel, E. and K. Henrick, Inference of macromolecular assemblies from crystalline state. J Mol Biol, Cerca con Google

2007. 372(3): p. 774-97. Cerca con Google

120. Lerner M. G., C., H. A. and A. Arbor:, APBS Plugin for PyMOL. 2006: University of Michigan. Cerca con Google

121. Bond, C.S. and A.W. Schuttelkopf, ALINE: a WYSIWYG protein-sequence alignment editor for Cerca con Google

publication-quality alignments. Acta Crystallogr D Biol Crystallogr, 2009. 65(Pt 5): p. 510-2. Cerca con Google

122. Tompa, P., The interplay between structure and function in intrinsically unstructured proteins. FEBS Cerca con Google

Lett, 2005. 579(15): p. 3346-54. Cerca con Google

123. Uversky, V.N., Biophysical Methods to Investigate Intrinsically Disordered Proteins: Avoiding an Cerca con Google

"Elephant and Blind Men" Situation. Adv Exp Med Biol, 2015. 870: p. 215-60. Cerca con Google

124. Uversky, V.N., Dancing Protein Clouds: The Strange Biology and Chaotic Physics of Intrinsically Cerca con Google

Disordered Proteins. J Biol Chem, 2016. 291(13): p. 6681-8. Cerca con Google

125. Mitrea, D.M., et al., Disorder-function relationships for the cell cycle regulatory proteins p21 and p27. Cerca con Google

Biol Chem, 2012. 393(4): p. 259-74. Cerca con Google

126. Csizmok, V., et al., Dynamic Protein Interaction Networks and New Structural Paradigms in Signaling. Cerca con Google

Chem Rev, 2016. 116(11): p. 6424-62. Cerca con Google

127. Meszaros, B., et al., Molecular principles of the interactions of disordered proteins. J Mol Biol, 2007. Cerca con Google

372(2): p. 549-61. Cerca con Google

128. Dunker, A.K., et al., Intrinsic disorder and protein function. Biochemistry, 2002. 41(21): p. 6573-82. Cerca con Google

129. Ball, K.A., D.E. Wemmer, and T. Head-Gordon, Comparison of Structure Determination Methods for Cerca con Google

Intrinsically Disordered Amyloid-β Peptides. The journal of physical chemistry. B, 2014. 118(24): p. Cerca con Google

6405-6416. Cerca con Google

130. Martino, A., et al., Structural characterisation, stability and antibody recognition of chimeric NHBAGNA1030: Cerca con Google

an investigational vaccine component against Neisseria meningitidis. Vaccine, 2012. 30(7): p. Cerca con Google

1330-42. Cerca con Google

131. Deller, M.C., L. Kong, and B. Rupp, Protein stability: a crystallographer's perspective. Acta Cerca con Google

Crystallographica Section F, 2016. 72(2): p. 72-95. Cerca con Google

132. Ramaraj, T., et al., Antigen-antibody interface properties: composition, residue interactions, and Cerca con Google

features of 53 non-redundant structures. Biochim Biophys Acta, 2012. 1824(3): p. 520-32. Cerca con Google

133. Mian, I.S., A.R. Bradwell, and A.J. Olson, Structure, function and properties of antibody binding sites. J Cerca con Google

Mol Biol, 1991. 217(1): p. 133-51. Cerca con Google

134. Kringelum, J.V., et al., Structural analysis of B-cell epitopes in antibody:protein complexes. Mol Cerca con Google

Immunol, 2013. 53(1-2): p. 24-34. Cerca con Google

135. Ofran, Y., A. Schlessinger, and B. Rost, Automated identification of complementarity determining Cerca con Google

regions (CDRs) reveals peculiar characteristics of CDRs and B cell epitopes. J Immunol, 2008. 181(9): p. Cerca con Google

6230-5. Cerca con Google

87 Cerca con Google

136. Peng, H.P., et al., Origins of specificity and affinity in antibody-protein interactions. Proc Natl Acad Sci U Cerca con Google

S A, 2014. 111(26): p. E2656-65. Cerca con Google

137. Wernimont, A. and A. Edwards, In situ proteolysis to generate crystals for structure determination: an Cerca con Google

update. PLoS One, 2009. 4(4): p. e5094. Cerca con Google

138. Wong, E.T., D. Na, and J. Gsponer, On the importance of polar interactions for complexes containing Cerca con Google

intrinsically disordered proteins. PLoS Comput Biol, 2013. 9(8): p. e1003192. Cerca con Google

139. Cehlar, O., et al., Crystallization and preliminary X-ray diffraction analysis of tau protein microtubulebinding Cerca con Google

motifs in complex with Tau5 and DC25 antibody Fab fragments. Acta Crystallogr Sect F Struct Cerca con Google

Biol Cryst Commun, 2012. 68(Pt 10): p. 1181-5. Cerca con Google

140. Sela-Culang, I., S. Alon, and Y. Ofran, A systematic comparison of free and bound antibodies reveals Cerca con Google

binding-related conformational changes. J Immunol, 2012. 189(10): p. 4890-9. Cerca con Google

141. Sotriffer, C.A., et al., Ligand-induced domain movement in an antibody Fab: molecular dynamics studies Cerca con Google

confirm the unique domain movement observed experimentally for Fab NC6.8 upon complexation and Cerca con Google

reveal its segmental flexibility. J Mol Biol, 1998. 278(2): p. 301-6. Cerca con Google

142. Sotriffer, C.A., et al., Elbow flexibility and ligand-induced domain rearrangements in antibody Fab Cerca con Google

NC6.8: large effects of a small hapten. Biophys J, 2000. 79(2): p. 614-28. Cerca con Google

143. Stanfield, R.L., et al., Antibody elbow angles are influenced by their light chain class. J Mol Biol, 2006. Cerca con Google

357(5): p. 1566-74. Cerca con Google

144. Keskin, O., Binding induced conformational changes of proteins correlate with their intrinsic Cerca con Google

fluctuations: a case study of antibodies. BMC Struct Biol, 2007. 7: p. 31. Cerca con Google

145. Sundberg, E.J., Structural basis of antibody-antigen interactions. Methods Mol Biol, 2009. 524: p. 23-36. Cerca con Google

146. Pötzsch, S., et al., B Cell Repertoire Analysis Identifies New Antigenic Domains on Glycoprotein B of Cerca con Google

Human Cytomegalovirus which Are Target of Neutralizing Antibodies. PLoS Pathog, 2011. 7(8): p. Cerca con Google

e1002172. Cerca con Google

147. Kabanova, A., et al., Antibody-driven design of a human cytomegalovirus gHgLpUL128L subunit vaccine Cerca con Google

that selectively elicits potent neutralizing antibodies. Proc Natl Acad Sci U S A, 2014. 111(50): p. 17965- Cerca con Google

70. Cerca con Google

148. Krause, J.C., et al., A broadly neutralizing human monoclonal antibody that recognizes a conserved, Cerca con Google

novel epitope on the globular head of the influenza H1N1 virus hemagglutinin. J Virol, 2011. 85(20): p. Cerca con Google

10905-8. Cerca con Google

149. Corti, D., et al., Analysis of Memory B Cell Responses and Isolation of Novel Monoclonal Antibodies with Cerca con Google

Neutralizing Breadth from HIV-1-Infected Individuals. PLoS ONE, 2010. 5(1): p. e8805. Cerca con Google

150. Uysal, S., et al., Crystal structure of full-length KcsA in its closed conformation. Proc Natl Acad Sci U S A, Cerca con Google

2009. 106(16): p. 6644-9. Cerca con Google

151. Granata, V., et al., Comparison of the crystallization and crystal packing of two Fab single-site mutant Cerca con Google

protein L complexes. Acta Crystallographica Section D, 2005. 61(6): p. 750-754. Cerca con Google

152. McKinstry, W.J., et al., Crystallization of the receptor-binding domain of parathyroid hormone-related Cerca con Google

protein in complex with a neutralizing monoclonal antibody Fab fragment. Acta Crystallogr Sect F Struct Cerca con Google

Biol Cryst Commun, 2009. 65(Pt 4): p. 336-8. Cerca con Google

153. Civril, F. and K.P. Hopfner, Crystallization of mouse RIG-I ATPase domain: in situ proteolysis. Methods Cerca con Google

Mol Biol, 2014. 1169: p. 27-35. Cerca con Google

154. Bai, Y., T.C. Auperin, and L. Tong, The use of in situ proteolysis in the crystallization of murine CstF-77. Cerca con Google

Acta Crystallogr Sect F Struct Biol Cryst Commun, 2007. 63(Pt 2): p. 135-8. Cerca con Google

155. Koth, C.M., et al., Use of limited proteolysis to identify protein domains suitable for structural analysis. Cerca con Google

Methods Enzymol, 2003. 368: p. 77-84. Cerca con Google

156. Hansen, J.C., et al., Intrinsic protein disorder, amino acid composition, and histone terminal domains. J Cerca con Google

Biol Chem, 2006. 281(4): p. 1853-6. Cerca con Google

88 Cerca con Google

157. Koide, S. and S.S. Sidhu, The importance of being tyrosine: lessons in molecular recognition from Cerca con Google

minimalist synthetic binding proteins. ACS Chem Biol, 2009. 4(5): p. 325-34. Cerca con Google

158. MacRaild, C.A., et al., Antibody Recognition of Disordered Antigens. Structure, 2016. 24(1): p. 148-57. Cerca con Google

159. Raveh, B., et al., Rosetta FlexPepDock ab-initio: simultaneous folding, docking and refinement of Cerca con Google

peptides onto their receptors. PLoS One, 2011. 6(4): p. e18934. Cerca con Google

160. Sircar, A. and J.J. Gray, SnugDock: paratope structural optimization during antibody-antigen docking Cerca con Google

compensates for errors in antibody homology models. PLoS Comput Biol, 2010. 6(1): p. e1000644. Cerca con Google

161. Ponomarenko, J.V. and P.E. Bourne, Antibody-protein interactions: benchmark datasets and prediction Cerca con Google

tools evaluation. BMC Struct Biol, 2007. 7: p. 64. Cerca con Google

162. Vajda, S., Classification of protein complexes based on docking difficulty. Proteins, 2005. 60(2): p. 176- Cerca con Google

80. Cerca con Google

163. Kringelum, J.V., et al., Reliable B Cell Epitope Predictions: Impacts of Method Development and Cerca con Google

Improved Benchmarking. PLoS Comput Biol, 2012. 8(12): p. e1002829. Cerca con Google

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