A polymorphic pocket at the P10 position contributes to peptide binding specificity in class II MHC proteins.
Peptides bind to class II major histocompatibility complex (MHC) proteins in an extended conformation. Pockets in the peptide binding site spaced to accommodate peptide side chains at the P1, P4, P6, and P9 positions have been previously characterized and help to explain the obtained peptide binding specificity. However, two peptides differing only at P10 have significantly different binding affinities for HLA-DR1. The structure of HLA-DR1 in complex with the tighter binding peptide shows that the peptide binds in the usual polyproline type II conformation, but with the P10 residue accommodated in a shallow pocket at the end of the binding groove. HLA-DR1 variants with polymorphic residues at these positions were produced and found to exhibit different side chain specificity at the P10 position. These results define a new specificity position in HLA-DR proteins.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Zarixia
Z
Zavala-Ruiz
Iwona
I
Strug
Matthew W
MW
Anderson
Jack
J
Gorski
Lawrence J
LJ
Stern
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D014644:Genetic Variation; D015798:HLA-DR1 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011485:Protein Binding / Q000235:genetics / Q000502:physiology
D015798:HLA-DR1 Antigen; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments