{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T16:05:06Z","timestamp":1789488306666,"version":"build-2803163510"},"reference-count":38,"publisher":"American Chemical Society (ACS)","issue":"36","license":[{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000288","name":"Royal Society","doi-asserted-by":"publisher","award":["220628\/Z\/20\/Z"],"award-info":[{"award-number":["220628\/Z\/20\/Z"]}],"id":[{"id":"10.13039\/501100000288","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["220628\/Z\/20\/Z"],"award-info":[{"award-number":["220628\/Z\/20\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000777","name":"University of Leeds","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000777","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>T-cell receptor (TCR)\u2013based therapeutics recognize specific peptides presented by human leukocyte antigens (HLAs) on antigen-presenting cells. The docking orientation of TCRs to peptide\u2013HLA (pHLA) complexes is critical for T-cell activation as it underpins signaling and downstream immune responses. Traditionally, TCR binding geometries with pHLAs have been resolved through X-ray crystallography. Here, we demonstrate that conventional peptide-level hydrogen\u2013deuterium exchange mass spectrometry (HDX-MS) workflows can identify productive TCR engagement with their cognate pHLAs. By quantifying differential deuterium uptake upon complex formation, we show that TCRs that bind centrally within the pHLA groove have distinct uptake profiles compared with those adopting alternative orientations. Comparison of uptake data with information from structure prediction further contextualized the HDX data for distinct TCR\u2013pHLA binding modes, thus highlighting the value of integrating experimental and computational approaches. Collectively, our findings establish existing HDX-MS workflows as rapid and accessible approaches for probing TCR\u2013pHLA interactions, with direct implications for the development of TCR-based biotherapeutics.<\/jats:p>","DOI":"10.1021\/acs.analchem.5c07287","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T12:00:12Z","timestamp":1788350412000},"page":"26299-26310","source":"Crossref","is-referenced-by-count":0,"title":["Mapping the\nTCR\u2013Peptide-HLA Interface through\nHydrogen\u2013Deuterium Exchange Mass Spectrometry"],"prefix":"10.1021","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8308-6510","authenticated-orcid":true,"given":"Thomas","family":"Powell","sequence":"first","affiliation":[{"name":"Immunocore Limited , 92 Park Drive, Milton Park , ,","place":["Abingdon, United Kingdom, OX14 4RY"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Colyer","sequence":"additional","affiliation":[{"name":"University of Leeds , , ,","place":["Leeds, United Kingdom, LS2 9JT"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Wildsmith","sequence":"additional","affiliation":[{"name":"University of Leeds , , ,","place":["Leeds, United Kingdom, LS2 9JT"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijaykumar","family":"Karuppiah","sequence":"additional","affiliation":[{"name":"Immunocore Limited , 92 Park Drive, Milton Park , ,","place":["Abingdon, United Kingdom, OX14 4RY"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saher Afshan","family":"Shaikh","sequence":"additional","affiliation":[{"name":"Immunocore Limited , 92 Park Drive, Milton Park , ,","place":["Abingdon, United Kingdom, OX14 4RY"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Ebner","sequence":"additional","affiliation":[{"name":"Immunocore Limited , 92 Park Drive, Milton Park , ,","place":["Abingdon, United Kingdom, OX14 4RY"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Creese","sequence":"additional","affiliation":[{"name":"Immunocore Limited , 92 Park Drive, Milton Park , ,","place":["Abingdon, United Kingdom, OX14 4RY"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2437-7761","authenticated-orcid":true,"given":"Antonio N.","family":"Calabrese","sequence":"additional","affiliation":[{"name":"University of Leeds , , ,","place":["Leeds, United Kingdom, LS2 9JT"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,29]]},"reference":[{"issue":"5","key":"2026091511073729100_cit1","doi-asserted-by":"publisher","first-page":"349","DOI":"10.4049\/immunohorizons.2100033","article-title":"Design of TCR Structural Variants That Retain or Invert the Normal\nActivation Signal","volume":"5","author":"Mock","year":"2021","journal-title":"ImmunoHorizons"},{"issue":"4","key":"2026091511073729100_cit2","doi-asserted-by":"publisher","first-page":"1480","DOI":"10.4049\/jimmunol.1501721","article-title":"The Length\nDistribution of Class\nI\u2013Restricted T Cell Epitopes Is Determined by Both Peptide\nSupply and MHC Allele\u2013Specific Binding Preference","volume":"196","author":"Trolle","year":"2016","journal-title":"J. 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Mass Spectrom."},{"key":"2026091511073729100_cit34","doi-asserted-by":"publisher","DOI":"10.3389\/frans.2023.1118749","article-title":"Hydrogen Deuterium\nExchange and Other Mass Spectrometry-\nBased Approaches for Epitope Mapping","volume":"3","author":"Jethva","year":"2023","journal-title":"Front.\nAnal. Sci."},{"issue":"1","key":"2026091511073729100_cit35","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2023.2285285","article-title":"Epitope\nMapping of Monoclonal Antibodies: A Comprehensive Comparison of Different\nTechnologies","volume":"15","author":"Dang","year":"2023","journal-title":"mAbs"},{"key":"2026091511073729100_cit36","doi-asserted-by":"crossref","unstructured":"Lin, D.; Magalhaes, L. G.; McMillan, J.; Eadsforth, T. C.; Stewart, G.; Cartmill, K.; Postis, V.; Masson, G.\n          Spatially Resolved\nDetermination of Small Molecule Protein Affinities by Hydrogen Deuterium\nExchange Mass Spectrometry\n          bioRxiv\n          2025\n          10.1101\/2025.11.13.688232.","DOI":"10.1101\/2025.11.13.688232"},{"issue":"10","key":"2026091511073729100_cit37","doi-asserted-by":"publisher","first-page":"2315","DOI":"10.1021\/jasms.5c00229","article-title":"Site-Specific\nHydrogen Deuterium\nExchange Difference Mass Spectrometry Measurements for Ligand Binding","volume":"36","author":"Anacleto","year":"2025","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"2026091511073729100_cit38","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1177\/14690667251339717","article-title":"Tandem Mass\nSpectrometry Fragmentation\nPatterns of Sulfo-SDA Cross-Linked Peptides","volume":"31","author":"Powell","year":"2025","journal-title":"Eur. J. 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