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The voltage sensor-like domain (VSLD) is a major site of pharmacological modulation, but the molecular determinants of ligand recognition and efficacy remain incompletely understood. Here we combine cryo-electron microscopy, molecular dynamics simulations, mutagenesis, and medicinal chemistry to investigate the interactions of TRPM3 with the inhibitors isosakuranetin, maprotiline, and diclofenac. We show that structurally diverse ligands occupy a common VSLD cavity but engage distinct interaction networks. Functional and computational analyses identify ligand-specific residue dependencies and support a halogen bond between diclofenac and D947 that contributes to inhibitor potency. Furthermore, esterification or amidation of the diclofenac carboxylate converts inhibition into potentiation, and mutagenesis and molecular dynamics simulations support partially overlapping VSLD configurations associated with these opposing effects. Together, these findings establish the TRPM3 VSLD as an adaptable allosteric pocket in which ligand-specific interactions shape recognition, potency, and efficacy.<\/jats:p>","DOI":"10.64898\/2026.09.27.753811","type":"posted-content","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:20:15Z","timestamp":1790828415000},"source":"Crossref","is-referenced-by-count":0,"title":["Molecular determinants of ligand recognition and efficacy in the TRPM3 voltage sensor-like domain"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5000-8903","authenticated-orcid":false,"given":"Vikram","family":"Dalal","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9721-6195","authenticated-orcid":false,"given":"Vipin A.","family":"Rangari","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"Center for Clinical Pharmacology and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4290-0177","authenticated-orcid":false,"given":"Samuel","family":"Eriksson Lidbrink","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, SciLifeLab, Stockholm University, Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Trent","family":"Moreland","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2734-2794","authenticated-orcid":false,"given":"Erik","family":"Lindahl","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, SciLifeLab, Stockholm University, Solna, Sweden"},{"name":"Department of Applied Physics, SciLifeLab, KTH Royal Institute of Technology, Solna, Sweden"},{"name":"Department of Physics, Chemistry and Biology, Link\u00f6ping University, Link\u00f6ping, Sweden"},{"name":"Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2049-3378","authenticated-orcid":false,"given":"Rebecca J.","family":"Howard","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, SciLifeLab, Stockholm University, Solna, Sweden"},{"name":"Department of Applied Physics, SciLifeLab, KTH Royal Institute of Technology, Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2931-3823","authenticated-orcid":false,"given":"Susruta","family":"Majumdar","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"Center for Clinical Pharmacology and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9529-9820","authenticated-orcid":false,"given":"Wayland W. 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