Crystal structure of the Frizzled 4 receptor in a ligand-free state

Shifan Yang, Yiran Wu, Ting-Hai Xu, Parker W. Waal, Yuanzheng He, Mengchen Pu, Yuxiang Chen, Zachary J. DeBruine, Bingjie Zhang, Saheem A. Zaidi, Petr Popov, Yu Guo, Gye Won Han, Yang Lu, Kelly Suino-Powell, Shaowei Dong, Kaleeckal G. Harikumar, Laurence J. Miller, Vsevolod Katritch, H. Eric Xu, Wenqing Shui, Raymond C. Stevens, Karsten Melcher, Suwen Zhao and Fei Xu ()
Additional contact information
Shifan Yang: iHuman Institute, ShanghaiTech University
Yiran Wu: iHuman Institute, ShanghaiTech University
Ting-Hai Xu: Innovation and Integration Program, Van Andel Research Institute
Parker W. Waal: Innovation and Integration Program, Van Andel Research Institute
Yuanzheng He: Harbin Institute of Technology
Mengchen Pu: iHuman Institute, ShanghaiTech University
Yuxiang Chen: iHuman Institute, ShanghaiTech University
Zachary J. DeBruine: Innovation and Integration Program, Van Andel Research Institute
Bingjie Zhang: iHuman Institute, ShanghaiTech University
Saheem A. Zaidi: University of Southern California
Petr Popov: University of Southern California
Yu Guo: iHuman Institute, ShanghaiTech University
Gye Won Han: University of Southern California
Yang Lu: Harbin Institute of Technology
Kelly Suino-Powell: Innovation and Integration Program, Van Andel Research Institute
Shaowei Dong: iHuman Institute, ShanghaiTech University
Kaleeckal G. Harikumar: Mayo Clinic
Laurence J. Miller: Mayo Clinic
Vsevolod Katritch: University of Southern California
H. Eric Xu: Innovation and Integration Program, Van Andel Research Institute
Wenqing Shui: iHuman Institute, ShanghaiTech University
Raymond C. Stevens: iHuman Institute, ShanghaiTech University
Karsten Melcher: Innovation and Integration Program, Van Andel Research Institute
Suwen Zhao: iHuman Institute, ShanghaiTech University
Fei Xu: iHuman Institute, ShanghaiTech University

Nature, 2018, vol. 560, issue 7720, 666-670

Abstract: Abstract Frizzled receptors (FZDs) are class-F G-protein-coupled receptors (GPCRs) that function in Wnt signalling and are essential for developing and adult organisms1,2. As central mediators in this complex signalling pathway, FZDs serve as gatekeeping proteins both for drug intervention and for the development of probes in basic and in therapeutic research. Here we present an atomic-resolution structure of the human Frizzled 4 receptor (FZD4) transmembrane domain in the absence of a bound ligand. The structure reveals an unusual transmembrane architecture in which helix VI is short and tightly packed, and is distinct from all other GPCR structures reported so far. Within this unique transmembrane fold is an extremely narrow and highly hydrophilic pocket that is not amenable to the binding of traditional GPCR ligands. We show that such a pocket is conserved across all FZDs, which may explain the long-standing difficulties in the development of ligands for these receptors. Molecular dynamics simulations on the microsecond timescale and mutational analysis uncovered two coupled, dynamic kinks located at helix VII that are involved in FZD4 activation. The stability of the structure in its ligand-free form, an unfavourable pocket for ligand binding and the two unusual kinks on helix VII suggest that FZDs may have evolved a novel ligand-recognition and activation mechanism that is distinct from that of other GPCRs.

Date: 2018
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DOI: 10.1038/s41586-018-0447-x

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