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 Xu & 5 others Wenqing Shui, Raymond C. Stevens, Karsten Melcher, Suwen Zhao, Fei Xu

Research output: Contribution to journalLetter

10 Citations (Scopus)

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

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Frizzled Receptors
G-Protein-Coupled Receptors
Ligands
Gatekeeping
Mediator Complex
Therapeutic Human Experimentation
Molecular Dynamics Simulation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

Cite this

Yang, S., Wu, Y., Xu, T. H., de Waal, P. W., He, Y., Pu, M., ... 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

Crystal structure of the Frizzled 4 receptor in a ligand-free state. / Yang, Shifan; Wu, Yiran; Xu, Ting Hai; de Waal, Parker W.; He, Yuanzheng; Pu, Mengchen; Chen, Yuxiang; DeBruine, Zachary J.; Zhang, Bingjie; Zaidi, Saheem A.; Popov, Petr; Guo, Yu; Han, Gye Won; Lu, Yang; Suino-Powell, Kelly; Dong, Shaowei; Harikumar, Kaleeckal G.; Miller, Laurence J; Katritch, Vsevolod; Xu, H. Eric; Shui, Wenqing; Stevens, Raymond C.; Melcher, Karsten; Zhao, Suwen; Xu, Fei.

In: Nature, Vol. 560, No. 7720, 30.08.2018, p. 666-670.

Research output: Contribution to journalLetter

Yang, S, Wu, Y, Xu, TH, de Waal, PW, He, Y, Pu, M, Chen, Y, DeBruine, ZJ, Zhang, B, Zaidi, SA, Popov, P, Guo, Y, Han, GW, Lu, Y, Suino-Powell, K, Dong, S, Harikumar, KG, Miller, LJ, Katritch, V, Xu, HE, Shui, W, Stevens, RC, Melcher, K, Zhao, S & Xu, F 2018, 'Crystal structure of the Frizzled 4 receptor in a ligand-free state', Nature, vol. 560, no. 7720, pp. 666-670. https://doi.org/10.1038/s41586-018-0447-x
Yang S, Wu Y, Xu TH, de Waal PW, He Y, Pu M et al. Crystal structure of the Frizzled 4 receptor in a ligand-free state. Nature. 2018 Aug 30;560(7720):666-670. https://doi.org/10.1038/s41586-018-0447-x
Yang, Shifan ; Wu, Yiran ; Xu, Ting Hai ; de Waal, Parker W. ; He, Yuanzheng ; Pu, Mengchen ; Chen, Yuxiang ; DeBruine, Zachary J. ; Zhang, Bingjie ; Zaidi, Saheem A. ; Popov, Petr ; Guo, Yu ; Han, Gye Won ; Lu, Yang ; Suino-Powell, Kelly ; Dong, Shaowei ; Harikumar, Kaleeckal G. ; Miller, Laurence J ; Katritch, Vsevolod ; Xu, H. Eric ; Shui, Wenqing ; Stevens, Raymond C. ; Melcher, Karsten ; Zhao, Suwen ; Xu, Fei. / Crystal structure of the Frizzled 4 receptor in a ligand-free state. In: Nature. 2018 ; Vol. 560, No. 7720. pp. 666-670.
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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.",
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T1 - Crystal structure of the Frizzled 4 receptor in a ligand-free state

AU - Yang, Shifan

AU - Wu, Yiran

AU - Xu, Ting Hai

AU - de Waal, Parker W.

AU - He, Yuanzheng

AU - Pu, Mengchen

AU - Chen, Yuxiang

AU - DeBruine, Zachary J.

AU - Zhang, Bingjie

AU - Zaidi, Saheem A.

AU - Popov, Petr

AU - Guo, Yu

AU - Han, Gye Won

AU - Lu, Yang

AU - Suino-Powell, Kelly

AU - Dong, Shaowei

AU - Harikumar, Kaleeckal G.

AU - Miller, Laurence J

AU - Katritch, Vsevolod

AU - Xu, H. Eric

AU - Shui, Wenqing

AU - Stevens, Raymond C.

AU - Melcher, Karsten

AU - Zhao, Suwen

AU - Xu, Fei

PY - 2018/8/30

Y1 - 2018/8/30

N2 - 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.

AB - 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.

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SN - 0028-0836

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