Structural definition of the H-2Kd peptide-binding motif.
Classic major histocompatibility complex (MHC) proteins associate with antigen- and self-derived peptides in an allele-specific manner. Herein we present the crystal structure of the MHC class I protein H-2K(d) (K(d)) expressed by BALB/c mice in complex with an antigenic peptide derived from influenza A/PR/8/34 nucleoprotein (Flu, residues 147-155, TYQRTRALV). Analysis of our structure in conjunction with the sequences of naturally processed epitopes provides a comprehensive understanding of the dominant K(d) peptide-binding motif. We find that Flu residues Tyr(P2), Thr(P5), and Val(P9) are sequestered into the B, C, and F pockets of the K(d) groove, respectively. The shape and chemistry of the polymorphic B pocket make it an optimal binding site for the side chain of Tyr(P2) as the dominant anchoring residue of nonameric peptides. The non-polar F pocket limits the amino acid repertoire at P9 to hydrophobic residues such as Ile, Leu, or Val, whereas the C pocket restricts the size of the P5-anchoring side chain. We also show that Flu is accommodated in the complex through an unfavorable kink in the otherwise extended peptide backbone due to the presence of a prominent ridge in the K(d) groove. Surprisingly, this backbone conformation is strikingly similar to D(b)-presented peptides despite the fact that these proteins employ distinct motif-anchoring strategies. The results presented in this study provide a solid foundation for the understanding of K(d)-restricted antigen presentation and recognition events.
Mitaksov
Vesselin
V
Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Fremont
Daved H
DH
D000483:Alleles; D020816:Amino Acid Motifs; D000818:Animals; D017951:Antigen Presentation; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004583:Electrons; D004591:Electrophoresis, Polyacrylamide Gel; D000939:Epitopes; D006183:H-2 Antigens / Q000737:chemistry*; D006680:HLA Antigens / Q000737:chemistry*; D006860:Hydrogen Bonding; D009980:Influenza A virus / Q000378:metabolism; D007532:Isoleucine / Q000737:chemistry; D007700:Kinetics; D007930:Leucine / Q000737:chemistry; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D008958:Models, Molecular; D009698:Nucleoproteins / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012997:Solvents; D013499:Surface Properties; D014633:Valine / Q000737:chemistry; D014961:X-Ray Diffraction
D000939:Epitopes; D006183:H-2 Antigens; D006680:HLA Antigens; D009698:Nucleoproteins; D010455:Peptides; D012997:Solvents; D007532:Isoleucine; D007930:Leucine; D014633:Valine