Your browser doesn't support javascript.
loading
Structural insights into the human niacin receptor HCA2-Gi signalling complex.
Yang, Yang; Kang, Hye Jin; Gao, Ruogu; Wang, Jingjing; Han, Gye Won; DiBerto, Jeffrey F; Wu, Lijie; Tong, Jiahui; Qu, Lu; Wu, Yiran; Pileski, Ryan; Li, Xuemei; Zhang, Xuejun Cai; Zhao, Suwen; Kenakin, Terry; Wang, Quan; Stevens, Raymond C; Peng, Wei; Roth, Bryan L; Rao, Zihe; Liu, Zhi-Jie.
Afiliação
  • Yang Y; iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • Kang HJ; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • Gao R; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • Wang J; Department of Pharmacology, and NIMH Psychoactive Drug Screening Program University of North Carolina Chapel Hill Medical School, Chapel Hill, NC, 27514, USA.
  • Han GW; Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea.
  • DiBerto JF; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • Wu L; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • Tong J; iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • Qu L; Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA, 90089, USA.
  • Wu Y; Department of Pharmacology, and NIMH Psychoactive Drug Screening Program University of North Carolina Chapel Hill Medical School, Chapel Hill, NC, 27514, USA.
  • Pileski R; iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • Li X; iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • Zhang XC; iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • Zhao S; iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • Kenakin T; Department of Pharmacology, and NIMH Psychoactive Drug Screening Program University of North Carolina Chapel Hill Medical School, Chapel Hill, NC, 27514, USA.
  • Wang Q; Department of Obstetrics and Gynecology, Duke University, Durham, NC, USA.
  • Stevens RC; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • Peng W; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • Roth BL; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • Rao Z; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • Liu ZJ; iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
Nat Commun ; 14(1): 1692, 2023 03 27.
Article em En | MEDLINE | ID: mdl-36973264
ABSTRACT
The hydroxycarboxylic acid receptor 2 (HCA2) agonist niacin has been used as treatment for dyslipidemia for several decades albeit with skin flushing as a common side-effect in treated individuals. Extensive efforts have been made to identify HCA2 targeting lipid lowering agents with fewer adverse effects, despite little being known about the molecular basis of HCA2 mediated signalling. Here, we report the cryo-electron microscopy structure of the HCA2-Gi signalling complex with the potent agonist MK-6892, along with crystal structures of HCA2 in inactive state. These structures, together with comprehensive pharmacological analysis, reveal the ligand binding mode and activation and signalling mechanisms of HCA2. This study elucidates the structural determinants essential for HCA2 mediated signalling and provides insights into ligand discovery for HCA2 and related receptors.
Assuntos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Niacina Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Niacina Idioma: En Ano de publicação: 2023 Tipo de documento: Article