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Structure paper

TitleMolecular basis of neurosteroid and anticonvulsant regulation of TRPM3.
Journal, issue, pagesNat Struct Mol Biol, Vol. 32, Issue 5, Page 828-840, Year 2025
Publish dateJan 14, 2025
AuthorsYing Yin / Cheon-Gyu Park / Shasha Feng / Ziqiang Guan / Hyuk-Joon Lee / Feng Zhang / Kedar Sharma / Mario J Borgnia / Wonpil Im / Seok-Yong Lee /
PubMed AbstractTransient receptor potential channel subfamily M member 3 (TRPM3) is a Ca-permeable cation channel activated by the neurosteroid pregnenolone sulfate (PregS) or heat, serving as a nociceptor in the ...Transient receptor potential channel subfamily M member 3 (TRPM3) is a Ca-permeable cation channel activated by the neurosteroid pregnenolone sulfate (PregS) or heat, serving as a nociceptor in the peripheral sensory system. Recent discoveries of autosomal dominant neurodevelopmental disorders caused by gain-of-function mutations in TRPM3 highlight its role in the central nervous system. Notably, the TRPM3 inhibitor primidone, an anticonvulsant, has proven effective in treating patients with TRPM3-linked neurological disorders and in mouse models of thermal nociception. However, our understanding of neurosteroids, inhibitors and disease mutations on TRPM3 is limited. Here we present cryogenic electron microscopy structures of the mouse TRPM3 in complex with cholesteryl hemisuccinate, primidone and PregS with the synthetic agonist CIM 0216. Our studies identify the binding sites for the neurosteroid, synthetic agonist and inhibitor and offer insights into their effects and disease mutations on TRPM3 gating, aiding future drug development.
External linksNat Struct Mol Biol / PubMed:39809942 / PubMed Central
MethodsEM (single particle)
Resolution3.13 - 3.82 Å
Structure data

44100

9b28

EMDB-44100, PDB-9b28:
Cryo-EM structure of the mouse TRPM3 alpha 2 channel in complex with primidone
Method: EM (single particle) / Resolution: 3.24 Å

44101

9b29

EMDB-44101, PDB-9b29:
Cryo-EM structure of the mouse TRPM3 alpha 2 channel in complex with cholesteryl hemisuccinate
Method: EM (single particle) / Resolution: 3.13 Å

44102

9b2a

EMDB-44102, PDB-9b2a:
Cryo-EM structure of the mouse TRPM3 alpha 2 channel in complex with the neurosteroid pregnenolone sulfate and the synthetic agonist CIM 0216
Method: EM (single particle) / Resolution: 3.82 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-6OU:
[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate / phospholipid*YM

PDB-1aia:
STRUCTURAL BASIS FOR THE CATALYTIC ACTIVITY OF ASPARTATE AMINOTRANSFERASE K258H LACKING THE PYRIDOXAL-5'-PHOSPHATE BINDING LYSINE RESIDUE

ChemComp-LBN:
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / phospholipid*YM

ChemComp-PX2:
1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE

PDB-1aib:
STRUCTURAL BASIS FOR THE CATALYTIC ACTIVITY OF ASPARTATE AMINOTRANSFERASE K258H LACKING THE PYRIDOXAL-5'-PHOSPHATE BINDING LYSINE RESIDUE

ChemComp-A8W:
Pregnenolone sulfate / antidepressant*YM

Source
  • mus musculus (house mouse)
KeywordsTRANSPORT PROTEIN / Transient receptor potential channel / TRPM3 / neurosteroid / pregnenolone sulfate / neurodevelopmental disorders / anticonvulsant / primidone / neurological disorders / nociception / analgesic

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