5JZI

Crystal structure of 1406 TCR bound to HLA-A2 with HCV 1406-1415 antigen peptide

Replaces:  4ZEZ

Summary for 5JZI

• Entry DOI: 10.2210/pdb5jzi/pdb
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, KLV peptide, ... (6 entities in total)
• Functional Keywords: hcv1406 tcr, hla-a2, hcv ns3:1406-1415 peptide, decapeptide, protein binding, immune system complex, protein binding-immune system complex, protein binding/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 10
• Total formula weight: 193365.12

Authors

Wang, Y.,Piepenbrink, K.H.,Baker, B.M. (deposition date: 2016-05-16, release date: 2017-05-31, Last modification date: 2024-10-23)

Primary citation

Wang, Y.,Singh, N.K.,Spear, T.T.,Hellman, L.M.,Piepenbrink, K.H.,McMahan, R.H.,Rosen, H.R.,Vander Kooi, C.W.,Nishimura, M.I.,Baker, B.M.
How an alloreactive T-cell receptor achieves peptide and MHC specificity.
Proc. Natl. Acad. Sci. U.S.A., 114:E4792-E4801, 2017

PubMed Abstract: T-cell receptor (TCR) allorecognition is often presumed to be relatively nonspecific, attributable to either a TCR focus on exposed major histocompatibility complex (MHC) polymorphisms or the degenerate recognition of allopeptides. However, paradoxically, alloreactivity can proceed with high peptide and MHC specificity. Although the underlying mechanisms remain unclear, the existence of highly specific alloreactive TCRs has led to their use as immunotherapeutics that can circumvent central tolerance and limit graft-versus-host disease. Here, we show how an alloreactive TCR achieves peptide and MHC specificity. The HCV1406 TCR was cloned from T cells that expanded when a hepatitis C virus (HCV)-infected HLA-A2 individual received an HLA-A2 liver allograft. HCV1406 was subsequently shown to recognize the HCV nonstructural protein 3 (NS3):1406-1415 epitope with high specificity when presented by HLA-A2. We show that NS3/HLA-A2 recognition by the HCV1406 TCR is critically dependent on features unique to both the allo-MHC and the NS3 epitope. We also find cooperativity between structural mimicry and a crucial peptide "hot spot" and demonstrate its role, along with the MHC, in directing the specificity of allorecognition. Our results help explain the paradox of specificity in alloreactive TCRs and have implications for their use in immunotherapy and related efforts to manipulate TCR recognition, as well as alloreactivity in general.

PubMed: 28572406
DOI: 10.1073/pnas.1700459114

Experimental method

X-RAY DIFFRACTION (2.5 Å)