Molecular determinants of ligand recognition and efficacy in the TRPM3 voltage sensor-like domain

Authors

Dalal, V., Rangari, V., Eriksson Lidbrink, S., Moreland, K. T., Lindahl, E., Howard, R. J., Majumdar, S., Cheng, W. W.-L.

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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 02 Oct 2026.

Stats

1-terrible, 9-excellent. How would you rate this preprint? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.