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Limited structural data for human TRPV1 (hTRPV1) bound to clinically relevant antagonists has constrained mechanistic insight. Using chemoinformatics-informed cryo-EM and BRET assays, we identify variable antagonist target engagement across diverse chemotypes, including failed clinical compounds. A structure of hTRPV1 bound to 6-iodo-dihydrocapsaicin shows how a single atom substitution converts an agonist into an antagonist. Additional structures with Asivatrep, Mavatrep, and JNJ-17203212 reveal vanilloid pocket plasticity and divergent interaction networks, including lipid co-binding. Mutagenesis of ligand-interacting residues further demonstrates distinct contributions to antagonist engagement. Despite this diversity, antagonists converge on a conserved inhibited state, showing high potency is maintained across flexible binding modes. These findings refine our understanding of hTRPV1 antagonism and inform strategies for next-generation analgesics with improved safety.<\/jats:p>","DOI":"10.64898\/2026.04.27.721197","type":"posted-content","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T01:15:27Z","timestamp":1777511727000},"source":"Crossref","is-referenced-by-count":0,"title":["Chemically diverse antagonists inhibit human TRPV1 through ligand-specific interaction networks"],"prefix":"10.64898","author":[{"given":"Kyle E.","family":"Lopez","sequence":"first","affiliation":[{"name":"School of Molecular Sciences, Arizona State University, 551 E. University Drive, Tempe, AZ 85287"},{"name":"The Biodesign Institute Virginia G. 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