5FA4: Structure of HLA-A2:01 with peptide Y16R

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 (POmega) and contained charged amino acids not more than 3 residues after the anchor amino acid at POmega, 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.
PDB ID: 5FA4Download
MMDB ID: 145728
PDB Deposition Date: 2015/12/10
Updated in MMDB: 2016/12
Experimental Method:
x-ray diffraction
Resolution: 2.4  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 5FA4: trimeric; determined by author and by software (PISA)
Molecular Components in 5FA4
Label Count Molecule
Proteins (3 molecules)
HLA Class I Histocompatibility Antigen, A-2 Alpha Chain(Gene symbol: HLA-A)
Molecule annotation
Beta-2-microglobulin(Gene symbol: B2M)
Molecule annotation
Peptide Y16r
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB