Crystal structure of the major histocompatibility complex class I H-2Kb molecule containing a single viral peptide: implications for peptide binding and T-cell receptor recognition. (original) (raw)

• Journal List
• Proc Natl Acad Sci U S A
• v.89(17); 1992 Sep 1
• PMC49927

Proc Natl Acad Sci U S A. 1992 Sep 1; 89(17): 8403–8407.

Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461.

Abstract

To study the structure of a homogenous major histocompatibility complex (MHC) class I molecule containing a single bound peptide, a complex of recombinant mouse H-2Kb, beta 2-microglobulin (beta 2m), and a fragment of the vesicular stomatitis virus (VSV) nuclear capsid protein, VSV-(N52-59) octapeptide (Arg-Gly-Tyr-Val-Tyr-Gln-Gly-Leu), was prepared by exploiting a high-yield bacterial expression system and in vitro cocomplex formation. The structure of mouse H-2Kb revealed its similarity to three human class I HLA molecules, consistent with the high primary sequence homology and common function of these peptide-presenting molecules. Electron density was located in the peptide-binding groove, to which a single peptide in a unique conformation was unambiguously fit. The peptide extends the length of the groove, parallel to the alpha-helices, and assumes an extended, mostly beta-strand conformation. The peptide is constrained within the groove by hydrogen bonding of its main-chain atoms and by contacts of its side chains with the H-2Kb molecule. The amino-terminal nitrogen atom of the peptide forms a hydrogen bond with the hydroxyl group of Tyr-171 of H-2Kb at one end of the groove, while the carboxyl-terminal oxygen forms a hydrogen bond with the hydroxyl group of Tyr-84 at the other end. Since the amino acids at both ends are conserved among human and mouse MHC molecules, this anchoring of each end of the peptide appears to be a general feature of peptide-MHC class I molecule binding and imposes restrictions on its length. The side chains of residues Tyr-3, Tyr-5, and Leu-8 of the VSV octapeptide fit into the interior of the H-2Kb molecule with no appreciable surface exposure, a finding in support of previous biological studies that showed the importance of these residues for binding. Thus, the basis for binding of specific peptide sequences to the MHC class I molecule is the steric restriction imposed on the peptide side chains by the architecture of the floor and sides of the groove. The side chains of Arg-1, Val-4, and Gln-6 and the main-chain of Gly-7 of the octapeptide are exposed on the surface of the complex, thus confirming their availability for T-cell receptor contact, as previously demonstrated by T-cell recognition experiments.

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• Townsend AR, Gotch FM, Davey J. Cytotoxic T cells recognize fragments of the influenza nucleoprotein. Cell. 1985 Sep;42(2):457–467. [PubMed] [Google Scholar]
• Falk K, Rötzschke O, Rammensee HG. Cellular peptide composition governed by major histocompatibility complex class I molecules. Nature. 1990 Nov 15;348(6298):248–251. [PubMed] [Google Scholar]
• van Bleek GM, Nathenson SG. The structure of the antigen-binding groove of major histocompatibility complex class I molecules determines specific selection of self-peptides. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11032–11036. [PMC free article] [PubMed] [Google Scholar]
• Falk K, Rötzschke O, Stevanović S, Jung G, Rammensee HG. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature. 1991 May 23;351(6324):290–296. [PubMed] [Google Scholar]
• Falk K, Rötzschke O, Rammensee HG. Cellular peptide composition governed by major histocompatibility complex class I molecules. Nature. 1990 Nov 15;348(6298):248–251. [PubMed] [Google Scholar]
• Nathenson SG, Uehara H, Ewenstein BM, Kindt TJ, Coligan JE. Primary structural: analysis of the transplantation antigens of the murine H-2 major histocompatibility complex. Annu Rev Biochem. 1981;50:1025–1052. [PubMed] [Google Scholar]
• Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. Structure of the human class I histocompatibility antigen, HLA-A2. Nature. 1987 Oct 8;329(6139):506–512. [PubMed] [Google Scholar]
• Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature. 1987 Oct 8;329(6139):512–518. [PubMed] [Google Scholar]
• Ajitkumar P, Geier SS, Kesari KV, Borriello F, Nakagawa M, Bluestone JA, Saper MA, Wiley DC, Nathenson SG. Evidence that multiple residues on both the alpha-helices of the class I MHC molecule are simultaneously recognized by the T cell receptor. Cell. 1988 Jul 1;54(1):47–56. [PubMed] [Google Scholar]
• Nathenson SG, Geliebter J, Pfaffenbach GM, Zeff RA. Murine major histocompatibility complex class-I mutants: molecular analysis and structure-function implications. Annu Rev Immunol. 1986;4:471–502. [PubMed] [Google Scholar]
• Shibata K, Imarai M, van Bleek GM, Joyce S, Nathenson SG. Vesicular stomatitis virus antigenic octapeptide N52-59 is anchored into the groove of the H-2Kb molecule by the side chains of three amino acids and the main-chain atoms of the amino terminus. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3135–3139. [PMC free article] [PubMed] [Google Scholar]
• Studier FW, Rosenberg AH, Dunn JJ, Dubendorff JW. Use of T7 RNA polymerase to direct expression of cloned genes. Methods Enzymol. 1990;185:60–89. [PubMed] [Google Scholar]
• Brünger AT, Kuriyan J, Karplus M. Crystallographic R factor refinement by molecular dynamics. Science. 1987 Jan 23;235(4787):458–460. [PubMed] [Google Scholar]
• Madden DR, Gorga JC, Strominger JL, Wiley DC. The structure of HLA-B27 reveals nonamer self-peptides bound in an extended conformation. Nature. 1991 Sep 26;353(6342):321–325. [PubMed] [Google Scholar]
• Garrett TP, Saper MA, Bjorkman PJ, Strominger JL, Wiley DC. Specificity pockets for the side chains of peptide antigens in HLA-Aw68. Nature. 1989 Dec 7;342(6250):692–696. [PubMed] [Google Scholar]
• Gorga JC, Madden DR, Prendergast JK, Wiley DC, Strominger JL. Crystallization and preliminary X-ray diffraction studies of the human major histocompatibility antigen HLA-B27. Proteins. 1992 Jan;12(1):87–90. [PubMed] [Google Scholar]
• Carbone FR, Bevan MJ. Induction of ovalbumin-specific cytotoxic T cells by in vivo peptide immunization. J Exp Med. 1989 Mar 1;169(3):603–612. [PMC free article] [PubMed] [Google Scholar]
• Schumacher TN, Heemels MT, Neefjes JJ, Kast WM, Melief CJ, Ploegh HL. Direct binding of peptide to empty MHC class I molecules on intact cells and in vitro. Cell. 1990 Aug 10;62(3):563–567. [PubMed] [Google Scholar]
• Henderson RA, Michel H, Sakaguchi K, Shabanowitz J, Appella E, Hunt DF, Engelhard VH. HLA-A2.1-associated peptides from a mutant cell line: a second pathway of antigen presentation. Science. 1992 Mar 6;255(5049):1264–1266. [PubMed] [Google Scholar]
• Wei ML, Cresswell P. HLA-A2 molecules in an antigen-processing mutant cell contain signal sequence-derived peptides. Nature. 1992 Apr 2;356(6368):443–446. [PubMed] [Google Scholar]
• Clark SS, Forman J. Allogeneic and associative recognition determinants of H-2 molecules. Transplant Proc. 1983 Dec;15(4):2090–2092. [PubMed] [Google Scholar]
• de Waal LP, Kast WM, Melvold RW, Melief CJ. Regulation of the cytotoxic T lymphocyte response against Sendai virus analyzed with H-2 mutants. J Immunol. 1983 Mar;130(3):1090–1096. [PubMed] [Google Scholar]

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