1pyw Citations

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

J. Biol. Chem. 278 44904-12 (2003)
Cited: 16 times
EuropePMC logo PMID: 12952957


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.

Articles - 1pyw mentioned but not cited (3)

  1. 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)
  2. An effective and effecient peptide binding prediction approach for a broad set of HLA-DR molecules based on ordered weighted averaging of binding pocket profiles. Shen WJ, Zhang S, Wong HS. Proteome Sci 11 S15 (2013)
  3. An automated framework for understanding structural variations in the binding grooves of MHC class II molecules. Yeturu K, Utriainen T, Kemp GJ, Chandra N. BMC Bioinformatics 11 Suppl 1 S55 (2010)

Reviews citing this publication (3)

Articles citing this publication (10)

  1. 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)
  2. 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)
  3. 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)
  4. 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)
  5. 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)
  6. 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)
  7. HLA-DP2 binding prediction by molecular dynamics simulations. Doytchinova I, Petkov P, Dimitrov I, Atanasova M, Flower DR. Protein Sci. 20 1918-1928 (2011)
  8. Well differentiated thyroid carcinoma is associated with human lymphocyte antigen D-related 11 in Eastern Hungarians: a case of changing circumstances. Juhasz F, Kozma L, Stenszky V, Gyory F, Luckas G, Farid NR. Cancer 104 1603-1608 (2005)
  9. 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)
  10. 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)