Molecular determinants of ligand recognition and efficacy in the TRPM3 voltage sensor-like domain
- 1Washington University School of Medicine
Abstract
Transient receptor potential melastatin 3 (TRPM3) is a calcium-permeable ion channel implicated in chronic pain and developmental and epileptic encephalopathies. 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.
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BibTeX
@misc{dalal2026molecular,
title = {{Molecular determinants of ligand recognition and efficacy in the TRPM3 voltage sensor-like domain}},
author = {V. Dalal and V. Rangari and S. Eriksson Lidbrink and K. T. Moreland and E. Lindahl and R. J. Howard and S. Majumdar and W. W.-L. Cheng},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.27.753811},
url = {https://www.biorxiv.org/content/10.64898/2026.09.27.753811v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Molecular determinants of ligand recognition and efficacy in the TRPM3 voltage sensor-like domain
AU - V. Dalal
AU - V. Rangari
AU - S. Eriksson Lidbrink
AU - K. T. Moreland
AU - E. Lindahl
AU - R. J. Howard
AU - S. Majumdar
AU - W. W.-L. Cheng
PY - 2026
DA - 2026/09/27
PB - bioRxiv
DO - 10.64898/2026.09.27.753811
UR - https://www.biorxiv.org/content/10.64898/2026.09.27.753811v1
AB - Transient receptor potential melastatin 3 (TRPM3) is a calcium-permeable ion channel implicated in chronic pain and developmental and epileptic encephalopathies. 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.
ER -