9B2A

Cryo-EM structure of the mouse TRPM3 alpha 2 channel in complex with the neurosteroid pregnenolone sulfate and the synthetic agonist CIM 0216

これはPDB形式変換不可エントリーです。

9B2A の概要

• エントリーDOI: 10.2210/pdb9b2a/pdb
• EMDBエントリー: 44102
• 分子名称: Transient receptor potential cation channel, subfamily M, member 3, (2S)-2-(3,4-dihydroquinolin-1(2H)-yl)-N-(5-methyl-1,2-oxazol-3-yl)-2-phenylacetamide, [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate, ... (4 entities in total)
• 機能のキーワード: transient receptor potential channel, trpm3, neurosteroid, pregnenolone sulfate, neurodevelopmental disorders, anticonvulsant, primidone, neurological disorders, nociception, analgesic, transport protein
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 800544.98

構造登録者

Yin, Y.,Park, C.G.,Feng, S.,Zhang, F.,Guan, Z.,Sharma, K.,Borgnia, M.J.,Im, W.,Lee, S.-Y. (登録日: 2024-03-14, 公開日: 2025-01-22, 最終更新日: 2025-05-28)

主引用文献

Yin, Y.,Park, C.G.,Feng, S.,Guan, Z.,Lee, H.J.,Zhang, F.,Sharma, K.,Borgnia, M.J.,Im, W.,Lee, S.Y.
Molecular basis of neurosteroid and anticonvulsant regulation of TRPM3.
Nat.Struct.Mol.Biol., 32:828-840, 2025

PubMed Abstract: 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.

PubMed: 39809942
DOI: 10.1038/s41594-024-01463-8

実験手法

ELECTRON MICROSCOPY (3.82 Å)