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Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 Å resolution

Saper, M. A. and Bjorkman, P. J. and Wiley, D. C. (1991) Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 Å resolution. Journal of Molecular Biology, 219 (2). pp. 277-319. ISSN 0022-2836. doi:10.1016/0022-2836(91)90567-P.

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The three-dimensional structure of the human histocompatibility antigen HLA-A2 was determined at 3.5 Å resolution by a combination of isomorphous replacement and iterative real-space averaging of two crystal forms. The monoclinic crystal form has now been refined by least-squares methods to an R-factor of 0.169 for data from 6 to 2.6 Å resolution. A superposition of the structurally similar domains found in the heterodimer, α_1 onto α_2 and α_3 onto β_2m, as well as the latter pair onto the ancestrally related immunoglobulin constant domain, reveals that differences are mainly in the turn regions. Structural features of the α_1 and α_2 domains, such as conserved salt-bridges that contribute to stability, specific loops that form contacts with other domains, and the antigen-binding groove formed from two adjacent helical regions on top of an eight-stranded β-sheet, are analyzed. The interfaces between the domains, especially those between β_2m and the HLA heavy chain presumably involved in β_2m exchange and heterodimer assembly, are described in detail. A detailed examination of the binding groove confirms that the solvent-accessible amino acid side-chains that are most polymorphic in mouse and human alleles fill up the central and widest portion of the binding groove, while conserved side-chains are clustered at the narrower ends of the groove. Six pockets or sub-sites in the antigen-binding groove, of diverse shape and composition, appear suited for binding side-chains from antigenic peptides. Three pockets contain predominantly non-polar atoms; but others, especially those at the extreme ends of the groove, have clusters of polar atoms in close proximity to the “extra” electron density in the binding site. A possible role for β_2m in stabilizing permissible peptide complexes during folding and assembly is presented.

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Bjorkman, P. J.0000-0002-2277-3990
Additional Information:© 1991 Elsevier Ltd. Received 3 September 1990, Accepted 2 January 1991. The work was supported by NIH grant R01 AI 17237 (1980–1987) and the Howard Hughes Medical Institute. We thank Anastasia Haykov for excellent technical assistance. We acknowledge contributions made by William Bennett and Boudjema Samraoui to the determination of the HLA-A2 structure at 3·5 A resolution (Bjorkman et al .. l987a), Professor Jack Strominger for his initial and continuing collaboration, and Tom Garrett for contributions to the refinement. We thank Drs Dean Mann (NIH), D. Michael Strong and James Wood (U.S. Naval Research Unit) and Don Giard (MIT cell culture facility) for provision of cells. The Pittsburgh Supercomputer Center provided computation time for portions of the refinement. The work was supported by NIH grant ROI AI 17237 (1980-1987) and the Howard Hughes Medical Institute. P.J.B. is a PEW Scholar and recipient of an Investigator Award from the Cancer Research Institute. The refined co-ordinates of HLA-A2 are available from the Brookhaven Protein Data Bank (entry 3HLA). Edited by R. Huber
Funding AgencyGrant Number
NIHR01 AI 17237
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Pew Charitable TrustUNSPECIFIED
Cancer Research InstituteUNSPECIFIED
Subject Keywords:HLA; crystal structure; peptide; β2-microglobulin; immune system
Issue or Number:2
Record Number:CaltechAUTHORS:20170406-080635528
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Official Citation:M.A. Saper, P.J. Bjorkman, D.C. Wiley, Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 Å resolution, Journal of Molecular Biology, Volume 219, Issue 2, 1991, Pages 277-319, ISSN 0022-2836, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:75780
Deposited By: Ruth Sustaita
Deposited On:06 Apr 2017 15:48
Last Modified:15 Nov 2021 16:36

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