PDBsum entry 5fa3

Immune system

PDB id: 5fa3

Contents

Protein chains

273 a.a.

99 a.a.

Ligands

GLY-LEU-LEU-PRO-GLU-LEU-PRO-ALA-VAL

GOL ×3

Waters ×257

References listed in PDB file

Key reference

• Title: Unconventional peptide presentation by major histocompatibility complex (mhc) class i allele hla-A02:01: Breaking confinement.
• Authors: S.G.Remesh, M.Andreatta, G.Ying, T.Kaever, M.Nielsen, C.Mcmurtrey, W.Hildebrand, B.Peters, D.M.Zajonc.
• Ref.: J Biol Chem, 2017, 292, 5262-5270.
• PubMed id: 28179428

Abstract

Peptide antigen presentation by major histocompatibility complex (MHC) class I proteins initiates CD8⁺ T cell-mediated immunity against pathogens and cancers. MHC I molecules typically bind peptides with 9 amino acids in length with both ends tucked inside the major A and F binding pockets. It has been known for a while that longer peptides can also bind by either bulging out of the groove in the middle of the peptide or by binding in a zigzag fashion inside the groove. In a recent study, we identified an alternative binding conformation of naturally occurring peptides from Toxoplasma gondii bound by HLA-A*02:01. These peptides were extended at the C terminus (PΩ) and contained charged amino acids not more than 3 residues after the anchor amino acid at PΩ, which enabled them to open the F pocket and expose their C-terminal extension into the solvent. Here, we show that the mechanism of F pocket opening is dictated by the charge of the first charged amino acid found within the extension. Although positively charged amino acids result in the Tyr-84 swing, amino acids that are negatively charged induce a not previously described Lys-146 lift. Furthermore, we demonstrate that the peptides with alternative binding modes have properties that fit very poorly to the conventional MHC class I pathway and suggest they are presented via alternative means, potentially including cross-presentation via the MHC class II pathway.