4QRQ

Crystal Structure of HLA B*0801 in complex with HSKKKCDEL

Summary for 4QRQ

• Entry DOI: 10.2210/pdb4qrq/pdb
• Related: 4QRP 4QRR 4QRS 4QRT
• Descriptor: HLA class I histocompatibility antigen, B-8 alpha chain, Beta-2-microglobulin, NS3-4A protein, ... (4 entities in total)
• Functional Keywords: hla b*0801, human hepatitis c virus, tcr, t cell, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 44898.61

Authors

Gras, S.,Berry, R.,Lucet, I.S.,Rossjohn, J. (deposition date: 2014-07-02, release date: 2014-11-12, Last modification date: 2023-09-20)

Primary citation

Nivarthi, U.K.,Gras, S.,Kjer-Nielsen, L.,Berry, R.,Lucet, I.S.,Miles, J.J.,Tracy, S.L.,Purcell, A.W.,Bowden, D.S.,Hellard, M.,Rossjohn, J.,McCluskey, J.,Bharadwaj, M.
An Extensive Antigenic Footprint Underpins Immunodominant TCR Adaptability against a Hypervariable Viral Determinant.
J.Immunol., 193:5402-5413, 2014

PubMed Abstract: Mutations in T cell epitopes are implicated in hepatitis C virus (HCV) persistence and can impinge on vaccine development. We recently demonstrated a narrow bias in the human TCR repertoire targeted at an immunodominant, but highly mutable, HLA-B*0801-restricted epitope ((1395)HSKKKCDEL(1403) [HSK]). To investigate if the narrow TCR repertoire facilitates CTL escape, structural and biophysical studies were undertaken, alongside comprehensive functional analysis of T cells targeted at the natural variants of HLA-B*0801-HSK in different HCV genotypes and quasispecies. Interestingly, within the TCR-HLA-B*0801-HSK complex, the TCR contacts all available surface-exposed residues of the HSK determinant. This broad epitope coverage facilitates cross-genotypic reactivity and recognition of common mutations reported in HCV quasispecies, albeit to a varying degree. Certain mutations did abrogate T cell reactivity; however, natural variants comprising these mutations are reportedly rare and transient in nature, presumably due to fitness costs. Overall, despite a narrow bias, the TCR accommodated frequent mutations by acting like a blanket over the hypervariable epitope, thereby providing effective viral immunity. Our findings simultaneously advance the understanding of anti-HCV immunity and indicate the potential for cross-genotype HCV vaccines.

PubMed: 25355921
DOI: 10.4049/jimmunol.1401357

Experimental method

X-RAY DIFFRACTION (1.7 Å)