期刊
NATURE CHEMICAL BIOLOGY
卷 16, 期 12, 页码 1368-+出版社
NATURE RESEARCH
DOI: 10.1038/s41589-020-0646-2
关键词
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资金
- CPRIT Core Facility Support Award [RP170644]
- Endowed Scholars Program in Medical Science of UT Southwestern Medical Center, NIH [P01 HL020948, R01 GM135343]
- Welch Foundation [I-1957]
- DDBrown Fellow of the Life Sciences Research Foundation
- Damon Runyon Cancer Research Foundation [DRR-53-19]
- Rita C. and William P. Clements, Jr Scholar in Biomedical Research at UT Southwestern Medical Center
Smoothened (SMO), a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. Sterols can bind to its extracellular cysteine-rich domain (CRD) and to several sites in the seven transmembrane helices (7-TMs) of SMO. However, the mechanism by which sterols regulate SMO via multiple sites is unknown. Here we determined the structures of SMO-G(i)complexes bound to the synthetic SMO agonist (SAG) and to 24(S),25-epoxycholesterol (24(S),25-EC). A novel sterol-binding site in the extracellular extension of TM6 was revealed to connect other sites in 7-TMs and CRD, forming an intramolecular sterol channel from the middle side of 7-TMs to CRD. Additional structures of two gain-of-function variants, SMOD384R and SMOG111C/I496C, showed that blocking the channel at its midpoints allows sterols to occupy the binding sites in 7-TMs, thereby activating SMO. These data indicate that sterol transport through the core of SMO is a major regulator of SMO-mediated signaling.
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