变构调节
信号转导
兴奋剂
生物
机制(生物学)
常染色体显性多囊肾病
多囊肾病
功能(生物学)
细胞生物学
受体
G蛋白偶联受体
肾
遗传学
哲学
认识论
作者
Shristi Pawnikar,Brenda S. Magenheimer,Ericka Nevarez Munoz,Robin L. Maser,Yinglong Miao
标识
DOI:10.1073/pnas.2113786119
摘要
Significance Mutations of polycystin-1 (PC1) are the major cause (85% of cases) of autosomal dominant polycystic kidney disease (ADPKD), which is the fourth leading cause of kidney failure. PC1 is thought to function as an atypical G protein-coupled receptor, yet the mechanism by which PC1 regulates G-protein signaling remains poorly understood. A significant portion of ADPKD mutations of PC1 encode a protein with defects in maturation or reduced function that may be amenable to functional rescue. In this work, we have combined complementary biochemical and cellular assay experiments and accelerated molecular simulations, which revealed an allosteric transduction pathway in activation of the PC1 C-terminal fragment. Our findings will facilitate future rational drug design efforts targeting the PC1 signaling function.
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