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

Shifan Yang, Yiran Wu, Ting Hai Xu, Parker W. de 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 XuWenqing Shui, Raymond C. Stevens, Karsten Melcher, Suwen Zhao, Fei Xu

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)666-670
Number of pages5
JournalNature
Volume560
Issue number7720
DOIs
StatePublished - Aug 30 2018

ASJC Scopus subject areas

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    Yang, S., Wu, Y., Xu, T. H., de Waal, P. W., He, Y., Pu, M., Chen, Y., DeBruine, Z. J., Zhang, B., Zaidi, S. A., Popov, P., Guo, Y., Han, G. W., Lu, Y., Suino-Powell, K., Dong, S., Harikumar, K. G., Miller, L. J., Katritch, V., ... Xu, F. (2018). Crystal structure of the Frizzled 4 receptor in a ligand-free state. Nature, 560(7720), 666-670. https://doi.org/10.1038/s41586-018-0447-x