title: Identifiying human MHC supertypes using bioinformatic methods.
abstract: Classification of MHC molecules into supertypes in terms of peptide-binding specificities is an important issue, with direct implications for the development of epitope-based vaccines with wide population coverage. In view of extremely high MHC polymorphism (948 class I and 633 class II HLA alleles) the experimental solution of this task is presently impossible. In this study, we describe a bioinformatics strategy for classifying MHC molecules into supertypes using information drawn solely from three-dimensional protein structure. Two chemometric techniques-hierarchical clustering and principal component analysis-were used independently on a set of 783 HLA class I molecules to identify supertypes based on structural similarities and molecular interaction fields calculated for the peptide binding site. Eight supertypes were defined: A2, A3, A24, B7, B27, B44, C1, and C4. The two techniques gave 77% consensus, i.e., 605 HLA class I alleles were classified in the same supertype by both methods. The proposed strategy allowed "supertype fingerprints" to be identified. Thus, the A2 supertype fingerprint is Tyr(9)/Phe(9), Arg(97), and His(114) or Tyr(116); the A3-Tyr(9)/Phe(9)/Ser(9), Ile(97)/Met(97) and Glu(114) or Asp(116); the A24-Ser(9) and Met(97); the B7-Asn(63) and Leu(81); the B27-Glu(63) and Leu(81); for B44-Ala(81); the C1-Ser(77); and the C4-Asn(77).
authors.affiliation: Edward Jenner Institute for Vaccine Research, Compton, Berkshire, United Kingdom.
authors.forename: Irini A
authors.initials: IA
authors.lastname: Doytchinova
authors.forename: Pingping
authors.initials: P
authors.lastname: Guan
authors.forename: Darren R
authors.initials: DR
authors.lastname: Flower
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D016172:DNA Fingerprinting / Q000379:methods; D006680:HLA Antigens / Q000145:classification* / Q000235:genetics / Q000378:metabolism; D015234:HLA-A Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000145:classification* / Q000235:genetics / Q000378:metabolism; D006650:Histocompatibility Testing / Q000379:methods*; D006801:Humans; D005810:Multigene Family / Q000276:immunology*; D025941:Protein Interaction Mapping / Q000379:methods
chemical_list: D006680:HLA Antigens; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I