Volume 31, No 12, Dec 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 12, December 2021: 1311-1314   |  Open Access

LETTERS TO THE EDITOR

Cryo-EM structure of constitutively active human Frizzled 7 in complex with heterotrimeric Gs

Lu Xu^1,2,3,4,† , Bo Chen^1,† , Hannes Schihada^5,† , Shane C. Wright^5,6,† , Ainoleena Turku^5,8 , Yiran Wu¹ , Gye-Won Han⁷ , Maria Kowalski-Jahn⁵ , Pawel Kozielewicz⁵ , Carl-Fredrik Bowin⁵ , Xianjun Zhang^1,2,3,4,7 , Chao Li^1,2,3,4 , Michel Bouvier⁶ , Gunnar Schulte^5,* , Fei Xu^1,2,3,4,*

¹iHuman Institute, ShanghaiTech University, Shanghai, China
²School of Life Science and Technology, ShanghaiTech University, Shanghai, China
³Center for Excellence in Molecular Cell Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
⁴University of Chinese Academy of Sciences, Beijing, China
⁵Section of Receptor Biology & Signaling, Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden
⁶Institute for Research in Immunology and Cancer, Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada
⁷Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA, USA
⁸Present address: Orion Pharma R&D, Espoo, Finland
^†These authors contributed equally: Lu Xu, Bo Chen, Hannes Schihada, Shane C. Wright
Correspondence: Gunnar Schulte(gunnar.schulte@ki.se)Fei Xu(xufei@shanghaitech.edu.cn)

Dear Editor,

The ten mammalian Frizzleds (FZD1–10) belong to the class F of G protein-coupled receptors (GPCRs) and mediate WNT signaling through interaction with transducer proteins including Dishevelled (DVL) or heterotrimeric G proteins.1 Their involvement in human disease has put FZDs at the forefront of drug targets, especially anti-cancer therapy.2 However, no drugs have been developed for efficient pharmacological modulation of FZDs, partially owing to the limited understanding of FZD structure and activation mechanisms.1,3 Among class F, FZD7 is intensively pursued due to its relevance in various tumor models, particularly in intestinal cancers.4 Detailed structures of the receptor complexes would allow for structure-guided discovery of new drug candidates. FZD1–10 share structural similarity with the related class F member Smoothened (SMO), which mediates Hedgehog signaling and is a validated target for cancer therapy.2 In an effort to understand the structural basis of FZD activation and transducer interaction, we solved the structure of human FZD7 in complex with heterotrimeric mini Gs (mGs).5

https://doi.org/10.1038/s41422-021-00525-6

FULL TEXT | PDF

Browse 919