Author
Listed:
- Chong Wang
(The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)
- Huixian Wu
(The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)
- Vsevolod Katritch
(The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)
- Gye Won Han
(The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)
- Xi-Ping Huang
(National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27514, USA)
- Wei Liu
(The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)
- Fai Yiu Siu
(The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)
- Bryan L. Roth
(National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27514, USA)
- Vadim Cherezov
(The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)
- Raymond C. Stevens
(The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)
Abstract
The smoothened (SMO) receptor, a key signal transducer in the hedgehog signalling pathway, is responsible for the maintenance of normal embryonic development and is implicated in carcinogenesis. It is classified as a class frizzled (class F) G-protein-coupled receptor (GPCR), although the canonical hedgehog signalling pathway involves the GLI transcription factors and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 Å resolution. Although the SMO receptor shares the seven-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulphide bonds. The ligand binds at the extracellular end of the seven-transmembrane-helix bundle and forms extensive contacts with the loops.
Suggested Citation
Chong Wang & Huixian Wu & Vsevolod Katritch & Gye Won Han & Xi-Ping Huang & Wei Liu & Fai Yiu Siu & Bryan L. Roth & Vadim Cherezov & Raymond C. Stevens, 2013.
"Structure of the human smoothened receptor bound to an antitumour agent,"
Nature, Nature, vol. 497(7449), pages 338-343, May.
Handle:
RePEc:nat:nature:v:497:y:2013:i:7449:d:10.1038_nature12167
DOI: 10.1038/nature12167
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Cited by:
- Yu Qian & Zhengxiong Ma & Zhenmei Xu & Yaning Duan & Yangjie Xiong & Ruixue Xia & Xinyan Zhu & Zongwei Zhang & Xinyu Tian & Han Yin & Jian Liu & Jing Song & Yang Lu & Anqi Zhang & Changyou Guo & Lihua, 2024.
"Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation,"
Nature Communications, Nature, vol. 15(1), pages 1-12, December.
- Kaihua Zhang & Hao Wu & Nicholas Hoppe & Aashish Manglik & Yifan Cheng, 2022.
"Fusion protein strategies for cryo-EM study of G protein-coupled receptors,"
Nature Communications, Nature, vol. 13(1), pages 1-11, December.
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