3LV3

Crystal structure of HLA-B*2705 complexed with a peptide derived from the human voltage-dependent calcium channel alpha1 subunit (residues 513-521)

Summary for 3LV3

• Entry DOI: 10.2210/pdb3lv3/pdb
• Related: 1OF2 1OGT 1UXS 1UXW 2A83 3CZF
• Descriptor: HLA class I histocompatibility antigen, B-27 alpha chain, Beta-2-microglobulin, 9-meric peptide from Voltage-dependent L-type calcium channel subunit alpha-1D, ... (5 entities in total)
• Functional Keywords: immune system, mhc (major histocompatibility complex), hla-b*2705, disulfide bond, glycoprotein, immune response, membrane, mhc i, transmembrane, amyloid, amyloidosis, disease mutation, glycation, immunoglobulin domain, secreted, calcium channel, voltage-gated channel
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P03989; Secreted: P61769; Membrane; Multi-pass membrane protein: Q01668
• Total number of polymer chains: 3
• Total formula weight: 45461.38

Authors

Loll, B.,Rueckert, C.,Saenger, W.,Uchanska-Ziegler, B.,Ziegler, A. (deposition date: 2010-02-19, release date: 2010-11-24, Last modification date: 2024-10-09)

Primary citation

Loll, B.,Ruckert, C.,Hee, C.S.,Saenger, W.,Uchanska-Ziegler, B.,Ziegler, A.
Loss of recognition by cross-reactive T cells and its relation to a C-terminus-induced conformational reorientation of an HLA-B*2705-bound peptide.
Protein Sci., 20:278-290, 2011

PubMed 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 α1 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 Å 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.

PubMed: 21280120
DOI: 10.1002/pro.559

Experimental method

X-RAY DIFFRACTION (1.94 Å)