{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T16:31:52Z","timestamp":1758817912581,"version":"3.41.2"},"reference-count":44,"publisher":"American Society for Microbiology","issue":"17","license":[{"start":{"date-parts":[[2017,9,1]],"date-time":"2017-09-01T00:00:00Z","timestamp":1504224000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31030030","81621091"],"award-info":[{"award-number":["31030030","81621091"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81622031"],"award-info":[{"award-number":["81622031"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004739","name":"Youth Innovation Promotion Association of the Chinese Academy of Sciences","doi-asserted-by":"publisher","award":["2015078"],"award-info":[{"award-number":["2015078"]}],"id":[{"id":"10.13039\/501100004739","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2017,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Given the limited set of T cell receptor (TCR) V genes that are used to create TCRs that are reactive to different ligands, such as major histocompatibility complex (MHC) class I, MHC class II, and MHC-like proteins (for example, MIC molecules and CD1 molecules), the V\u03b41 segment can be rearranged with D\u03b4-J\u03b4-C\u03b4 or J\u03b1-C\u03b1 segments to form classical \u03b3\u03b4TCRs or uncommon \u03b1\u03b2TCRs using a V\u03b41 segment (\u03b4\/\u03b1\u03b2TCR). Here we have determined two complex structures of the \u03b4\/\u03b1\u03b2TCRs (S19-2 and TU55) bound to different locus-disparate MHC class I molecules with HIV peptides (HLA-A*2402-Nef138-10 and HLA-B*3501-Pol448-9). The overall binding modes resemble those of classical \u03b1\u03b2TCRs but display a strong tilt binding geometry of the V\u03b41 domain toward the HLA \u03b11 helix, due to a conserved extensive interaction between the CDR1\u03b4 loop and the N-terminal region of the \u03b11 helix (mainly in position 62). The aromatic amino acids of the CDR1\u03b4 loop exploit different conformations (\u201caromatic ladder\u201d or \u201caromatic hairpin\u201d) to accommodate distinct MHC helical scaffolds. This tolerance helps to explain how a particular TCR V region can similarly dock onto multiple MHC molecules and thus may potentially explain the nature of TCR cross-reactivity. In addition, the length of the CDR3\u03b4 loop could affect the extent of tilt binding of the V\u03b41 domain, and adaptively, the pairing V\u03b2 domains adjust their mass centers to generate differential MHC contacts, hence probably ensuring TCR specificity for a certain peptide-MHC class I (pMHC-I). Our data have provided further structural insights into the TCR recognition of classical pMHC-I molecules, unifying cross-reactivity and specificity.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>The specificity of \u03b1\u03b2 T cell recognition is determined by the CDR loops of the \u03b1\u03b2TCR, and the general mode of binding of \u03b1\u03b2TCRs to pMHC has been established over the last decade. Due to the intrinsic genomic structure of the TCR \u03b1\/\u03b4 chain locus, some V\u03b4 segments can rearrange with the C\u03b1 segment, forming a hybrid V\u03b4C\u03b1V\u03b2C\u03b2 TCR, the \u03b4\/\u03b1\u03b2TCR. However, the basis for the molecular recognition of such TCRs of their ligands is elusive. Here an \u03b1\u03b2TCR using the V\u03b41 segment, S19-2, was isolated from an HIV-infected patient in an HLA-A*24:02-restricted manner. We then solved the crystal structures of the S19-2 TCR and another \u03b4\/\u03b1\u03b2TCR, TU55, bound to their respective ligands, revealing a conserved V\u03b41 binding feature. Further binding kinetics analysis revealed that the S19-2 and TU55 TCRs bind pHLA very tightly and in a long-lasting manner. Our results illustrate the mode of binding of a TCR using the V\u03b41 segment to its ligand, virus-derived pHLA.<\/jats:p>","DOI":"10.1128\/jvi.00725-17","type":"journal-article","created":{"date-parts":[[2017,6,15]],"date-time":"2017-06-15T00:40:24Z","timestamp":1497487224000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":12,"title":["Conserved V\u03b41 Binding Geometry in a Setting of Locus-Disparate pHLA Recognition by \u03b4\/\u03b1\u03b2 T Cell Receptors (TCRs): Insight into Recognition of HIV Peptides by TCRs"],"prefix":"10.1128","volume":"91","author":[{"given":"Yi","family":"Shi","sequence":"first","affiliation":[{"name":"CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China"},{"name":"University of Chinese Academy of Sciences, Beijing, China"},{"name":"Center for Influenza Research and Early-Warning (CASCIRE), Chinese Academy 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Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China"},{"name":"University of Chinese Academy of Sciences, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuansheng","family":"Liu","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China"},{"name":"University of Chinese Academy of Sciences, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Gao","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Cheng","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Pathogenic Microbiology and Immunology, 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