March 27, 2025: Adam Oken, Oregon Health and Sciences University
Автор: CryoEM Service Centers
Загружено: 2025-03-31
Просмотров: 184
Описание:
Small-Molecule Modulation of the P2X7 Receptor Revealed by Cryo-EM
P2X receptors are trimeric ATP-gated ion channels that play roles in numerous physiological and pathophysiological processes from asthma to hearing loss. Acting as a novel node of inflammation, the P2X7 receptor subtype is a prominent pharmaceutical target for atherosclerosis, neurodegeneration, and cancer. However, the molecular pharmacology of P2X7 activation and antagonism is not fully defined. Our data of the P2X7 receptor in apo, agonist-, and antagonist-bound states reveals numerous insights into its pharmacology. With our ligand-bound structures, we can define the molecular determinants of high-affinity agonism as well identify three distinct classes of P2X7 allosteric antagonists. Apo closed state structures reveal how a partially hydrated Na+ ion interacts with the channel pore and identifies how key differences in the classical allosteric pockets between rat, mouse, and human P2X7 receptors affects ortholog-specific pharmacology. Altogether, our structures illuminate the molecular determinants of P2X7 receptor function which can be leveraged to design small-molecule modulators with clinical significance.
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