3LV3: Crystal Structure Of Hla-B2705 Complexed With A Peptide Derived From The Human Voltage-Dependent Calcium Channel Alpha1 Subunit (Residues 513-521)

Citation:
Abstract
The human major histocompatibility complex class I antigen HLA-B*2705 binds several sequence-related peptides (pVIPR, RRKWRRWHL; pLPM2, RRRWRRLTV; pGR, RRRWHRWRL). Cross-reactivity of cytotoxic T cells (CTL) against these HLA-B*2705:peptide complexes seemed to depend on a particular peptide conformation that is facilitated by the engagement of a crucial residue within the binding groove (Asp116), associated with a noncanonical bulging-in of the middle portion of the bound peptide. We were interested whether a conformational reorientation of the ligand might contribute to the lack of cross-reactivity of these CTL with a peptide derived from voltage-dependent calcium channel alpha1 subunit (pCAC, SRRWRRWNR), in which the C-terminal peptide residue pArg9 could engage Asp116. Analyses of the HLA-B*2705:pCAC complex by X-ray crystallography at 1.94 A resolution demonstrated that the peptide had indeed undergone a drastic reorientation, leading it to adopt a canonical binding mode accompanied by the loss of molecular mimicry between pCAC and sequence-related peptides such as pVIPR, pLMP2, and pGR. This was clearly a consequence of interactions of pArg9 with Asp116 and other F-pocket residues. Furthermore, we observed an unprecedented reorientation of several additional residues of the HLA-B*2705 heavy chain near the N-terminal region of the peptide, including also the presence of double conformations of two glutamate residues, Glu63 and Glu163, on opposing sides of the peptide binding groove. Together with the Arg-Ser exchange at peptide position 1, there are thus multiple structural reasons that may explain the observed failure of pVIPR-directed, HLA-B*2705-restricted CTL to cross-react with HLA-B*2705:pCAC complexes.
PDB ID: 3LV3Download
MMDB ID: 86427
PDB Deposition Date: 2010/2/19
Updated in MMDB: 2010/12
Experimental Method:
x-ray diffraction
Resolution: 1.94  Å
Source Organism:
Similar Structures:
Biological Unit for 3LV3: trimeric; determined by author and by software (PISA)
Molecular Components in 3LV3
Label Count Molecule
Proteins (3 molecules)
1
HLA Class I Histocompatibility Antigen, B-27 Alpha Chain(Gene symbol: HLA-B)
Molecule annotation
1
Beta-2-microglobulin(Gene symbol: B2M)
Molecule annotation
1
9-meric Peptide From Voltage-dependent L-type Calcium Channel Subunit Alpha-1d(Gene symbol: CACNA1D)
Molecule annotation
Chemicals (3 molecules)
1
3
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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