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Exploration of the P6/P7 region of the peptide-binding site of the human class II major histocompatability complex protein HLA-DR1.

Zavala-Ruiz Z, Sundberg EJ, Stone JD, DeOliveira DB, Chan IC, Svendsen J, Mariuzza RA, Stern LJ
J Biol Chem 278 44904-12 (2003)
Cited: 30 times
EuropePMC logo PMID: 12952957

Abstract

Crystal structures of the class II major histocompatibilty complex (MHC) protein, HLA-DR1, generally show a tight fit between MHC and bound peptide except in the P6/P7 region of the peptide-binding site. In this region, there is a shallow water-filled pocket underneath the peptide and between the pockets that accommodate the P6 and P7 side chains. We investigated the properties of this pocket with the idea of engineering substitutions into the corresponding region of peptide antigens to increase their binding affinity for HLA-DR1. We investigated d-amino acids and N-alkyl modifications at both the P6 and P7 positions of the peptide and found that binding of peptides to HLA-DR1 could be increased by incorporating an N-methyl substitution at position 7 of the peptide. The crystal structure of HLA-DR1 bound to a peptide containing a P7 N-methyl alanine was determined. The N-methyl group orients in the P6/P7 pocket, displacing one of the waters usually bound in this pocket. The structure shows that the substitution does not alter the conformation of the bound peptide, which adopts the usual polyproline type II helix. An antigenic peptide carrying the N-methyl modification is taken up by antigen-presenting cells and loaded onto endogenous class II MHC molecules for presentation, and the resultant MHC-peptide complexes activate antigen-specific T-cells. These results suggest a possible strategy for increasing the affinity of weakly immunogenic peptides that might be applicable to the development of vaccines and diagnostic reagents.

Reviews - 1pyw mentioned but not cited (1)

  1. Conformational variation in structures of classical and non-classical MHCII proteins and functional implications. Painter CA, Stern LJ. Immunol Rev 250 144-157 (2012)

Articles - 1pyw mentioned but not cited (11)

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  4. A hairpin turn in a class II MHC-bound peptide orients residues outside the binding groove for T cell recognition. Zavala-Ruiz Z, Strug I, Walker BD, Norris PJ, Stern LJ. Proc Natl Acad Sci U S A 101 13279-13284 (2004)
  5. Electrostatic modifications of the human leukocyte antigen-DR P9 peptide-binding pocket and susceptibility to primary sclerosing cholangitis. Hov JR, Kosmoliaptsis V, Traherne JA, Olsson M, Boberg KM, Bergquist A, Schrumpf E, Bradley JA, Taylor CJ, Lie BA, Trowsdale J, Karlsen TH. Hepatology 53 1967-1976 (2011)
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Reviews citing this publication (2)

  1. Polyproline-II helix in proteins: structure and function. Adzhubei AA, Sternberg MJ, Makarov AA. J Mol Biol 425 2100-2132 (2013)
  2. Mechanistic understanding and significance of small peptides interaction with MHC class II molecules for therapeutic applications. Afridi S, Hoessli DC, Hameed MW. Immunol Rev 272 151-168 (2016)

Articles citing this publication (16)

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  2. A polymorphic pocket at the P10 position contributes to peptide binding specificity in class II MHC proteins. Zavala-Ruiz Z, Strug I, Anderson MW, Gorski J, Stern LJ. Chem Biol 11 1395-1402 (2004)
  3. Crystal structure of staphylococcal enterotoxin I (SEI) in complex with a human major histocompatibility complex class II molecule. Fernández MM, Guan R, Swaminathan CP, Malchiodi EL, Mariuzza RA. J Biol Chem 281 25356-25364 (2006)
  4. HLA-DM mediates epitope selection by a "compare-exchange" mechanism when a potential peptide pool is available. Ferrante A, Anderson MW, Klug CS, Gorski J. PLoS One 3 e3722 (2008)
  5. Peptide binding to the HLA-DRB1 supertype: a proteochemometrics analysis. Dimitrov I, Garnev P, Flower DR, Doytchinova I. Eur J Med Chem 45 236-243 (2010)
  6. BOLA-DRB3 gene polymorphisms influence bovine leukaemia virus infection levels in Holstein and Holstein × Jersey crossbreed dairy cattle. Carignano HA, Beribe MJ, Caffaro ME, Amadio A, Nani JP, Gutierrez G, Alvarez I, Trono K, Miretti MM, Poli MA. Anim Genet 48 420-430 (2017)
  7. Design of glycopeptides used to investigate class II MHC binding and T-cell responses associated with autoimmune arthritis. Andersson IE, Andersson CD, Batsalova T, Dzhambazov B, Holmdahl R, Kihlberg J, Linusson A. PLoS One 6 e17881 (2011)
  8. Quantum chemical analysis explains hemagglutinin peptide-MHC Class II molecule HLA-DRbeta1*0101 interactions. Cárdenas C, Villaveces JL, Bohórquez H, Llanos E, Suárez C, Obregón M, Patarroyo ME. Biochem Biophys Res Commun 323 1265-1277 (2004)
  9. A Newly Recognized Pairing Mechanism of the α- and β-Chains of the Chicken Peptide-MHC Class II Complex. Zhang L, Li X, Ma L, Zhang B, Meng G, Xia C. J Immunol 204 1630-1640 (2020)
  10. HLA-DP2 binding prediction by molecular dynamics simulations. Doytchinova I, Petkov P, Dimitrov I, Atanasova M, Flower DR. Protein Sci 20 1918-1928 (2011)
  11. Introduction of Non-natural Amino Acids Into T-Cell Epitopes to Mitigate Peptide-Specific T-Cell Responses. Azam A, Mallart S, Illiano S, Duclos O, Prades C, Maillère B. Front Immunol 12 637963 (2021)
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  13. A fragment-based docking simulation for investigating peptide-protein bindings. Liao JM, Wang YT, Wang YT, Lin CS. Phys Chem Chem Phys 19 10436-10442 (2017)
  14. Exploring the nature of the H-bonds between the human class II MHC protein, HLA-DR1 (DRB*0101) and the influenza virus hemagglutinin peptide, HA306-318, using the quantum theory of atoms in molecules. Aray Y, Aguilera-García R, Izquierdo DR. J Biomol Struct Dyn 37 48-64 (2019)
  15. Loading dynamics of one SARS-CoV-2-derived peptide into MHC-II revealed by kinetic models. Song K, Xu H, Da LT. Biophys J 122 1665-1677 (2023)
  16. Quantifying Significance of MHC II Residues. Fan Y, Lu R, Wang L, Andreatta M, Li SC. IEEE/ACM Trans Comput Biol Bioinform 11 17-25 (2014)


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