变构调节
AMPA受体
变构调节剂
化学
离子通道
致电离效应
配体门控离子通道
谷氨酸受体
生物物理学
生物化学
受体
生物
作者
W. Daniel Hale,Alejandra Montaño Romero,Cuauhtémoc U. Gonzalez,Vasanthi Jayaraman,Albert Y. Lau,Richard L. Huganir,Edward C. Twomey
标识
DOI:10.1038/s41594-024-01328-0
摘要
Abstract Excitatory neurotransmission is principally mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype ionotropic glutamate receptors (AMPARs). Negative allosteric modulators are therapeutic candidates that inhibit AMPAR activation and can compete with positive modulators to control AMPAR function through unresolved mechanisms. Here we show that allosteric inhibition pushes AMPARs into a distinct state that prevents both activation and positive allosteric modulation. We used cryo-electron microscopy to capture AMPARs bound to glutamate, while a negative allosteric modulator, GYKI-52466, and positive allosteric modulator, cyclothiazide, compete for control of the AMPARs. GYKI-52466 binds in the ion channel collar and inhibits AMPARs by decoupling the ligand-binding domains from the ion channel. The rearrangement of the ligand-binding domains ruptures the cyclothiazide site, preventing positive modulation. Our data provide a framework for understanding allostery of AMPARs and for rational design of therapeutics targeting AMPARs in neurological diseases.
科研通智能强力驱动
Strongly Powered by AbleSci AI