Three-dimensional structure of H-2Dd complexed with an immunodominant peptide

LI H, NATARAJAN K, MALCHIODI EL, MARGULIES DH, MARIUZZA RA.

JOURNAL OF MOLECULAR BIOLOGY

Año: 1998 vol. 283 p. 179 - 191

0022-2836

The crystal structure of the mouse major histocompatibility complex (MHC) class Imolecule H-2Dd with an immunodominant peptide, designated P18-I10 (RGPGRAFVTI),from human immunodeficiency virus envelope glycoprotein 120 was determined at 3.2A resolution. A novel orientation of the alpha3 domain of Dd relative to thealpha1/alpha2 domains results in significantly fewer contacts between alpha3 and beta2-microglobulin compared with other MHC class I proteins. Four out of tenpeptide residues (P2 Gly, P3 Pro, P5 Arg and P10 Ile) are nearly completelyburied in the Dd binding groove. This is consistent with previous findings thatDd exploits a four-residue binding motif comprising a glycine at P2, a proline atP3, a positively charged residue at P5, and a C-terminal hydrophobic residue atP9 or P10. The side-chain of P5 Arg is directed toward the floor of thepredominantly hydrophobic binding groove where it forms two salt bridges and one hydrogen bond with Dd residue Asp77. The selection of glycine at P2 appears to bedue to a narrowing of the B pocket, relative to that of other class I molecules, caused by Arg66 whose side-chain folds down into the binding cleft. Residue P3Pro of P18-I10 occupies part of pocket D, which in Dd is partially split by aprominent hydrophobic ridge in the floor of the binding groove formed by Trp97and Trp114. Residues P6 through P9 form a solvent-exposed bulge, with P7 Pheprotruding the most from the binding groove and thereby probably constituting amajor site of interaction with T cell receptors. A comparison of H-2Dd/P18-I10with other MHC class I/peptide complexes of known structure provides insightsinto the possible basis for the specificity of the natural killer cell receptorLy-49A for several related class I molecules.