9C2C

Cryo-EM structure of the human P2X1 receptor in the NF449-bound inhibited state

これはPDB形式変換不可エントリーです。

9C2C の概要

• エントリーDOI: 10.2210/pdb9c2c/pdb
• 関連するPDBエントリー: 9C2A 9C2B
• EMDBエントリー: 45152 45153 45154
• 分子名称: P2X purinoceptor 1, 2-acetamido-2-deoxy-beta-D-glucopyranose, 4,4',4'',4'''-{carbonylbis[azanediylbenzene-5,1,3-triylbis(carbonylazanediyl)]}tetra(benzene-1,3-disulfonic acid) (3 entities in total)
• 機能のキーワード: membrane protein, ion channel, ligand-gated ion channel, p2x receptor, allosteric antagonist
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 145083.16

構造登録者

Oken, A.C.,Lisi, N.E.,Ditter, I.A.,Shi, H.,Mansoor, S.E. (登録日: 2024-05-30, 公開日: 2024-10-09)

主引用文献

Oken, A.C.,Lisi, N.E.,Ditter, I.A.,Shi, H.,Nechiporuk, N.A.,Mansoor, S.E.
Cryo-EM structures of the human P2X1 receptor reveal subtype-specific architecture and antagonism by supramolecular ligand-binding.
Nat Commun, 15:8490-8490, 2024

PubMed Abstract: P2X receptors are a family of seven trimeric non-selective cation channels that are activated by extracellular ATP to play roles in the cardiovascular, neuronal, and immune systems. Although it is known that the P2X1 receptor subtype has increased sensitivity to ATP and fast desensitization kinetics, an underlying molecular explanation for these subtype-selective features is lacking. Here we report high-resolution cryo-EM structures of the human P2X1 receptor in the apo closed, ATP-bound desensitized, and the high-affinity antagonist NF449-bound inhibited states. The apo closed and ATP-bound desensitized state structures of human P2X1 define subtype-specific properties such as distinct pore architecture and ATP-interacting residues. The NF449-bound inhibited state structure of human P2X1 reveals that NF449 has a unique dual-ligand supramolecular binding mode at the interface of neighboring protomers, inhibiting channel activation by overlapping with the canonical P2X receptor ATP-binding site. Altogether, these data define the molecular pharmacology of the human P2X1 receptor laying the foundation for structure-based drug design.

PubMed: 39353889
DOI: 10.1038/s41467-024-52636-4

実験手法

ELECTRON MICROSCOPY (2.9 Å)