Article | Published:

Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain

Nature volume 511, pages 557562 (31 July 2014) | Download Citation

Abstract

Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate. Structural studies have been restricted to the amino-terminal extracellular domain, providing little understanding of the membrane-spanning signal transduction domain. Metabotropic glutamate receptor 5 is of considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiction and movement disorders. Here we report the crystal structure of the transmembrane domain of the human receptor in complex with the negative allosteric modulator, mavoglurant. The structure provides detailed insight into the architecture of the transmembrane domain of class C receptors including the precise location of the allosteric binding site within the transmembrane domain and key micro-switches which regulate receptor signalling. This structure also provides a model for all class C G-protein-coupled receptors and may aid in the design of new small-molecule drugs for the treatment of brain disorders.

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Primary accessions

Protein Data Bank

Data deposits

Co-ordinates and structure factors have been deposited in the Protein Data Bank under the accession code 4OO9.

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Acknowledgements

We thank R. Owen, J. Waterman and D. Axford at I24, Diamond Light Source, Oxford, UK for technical support. We thank C. G. Tate and other colleagues at Heptares Therapeutics Ltd for suggestions and comments, specifically K. Hollenstein and R. Cheng for contributions to the crystallography, and J. Christopher and G. Brown for sourcing allosteric ligands.

Author information

Author notes

    • Andrew S. Doré
    • , Krzysztof Okrasa
    • , Jayesh C. Patel
    •  & Maria Serrano-Vega

    These authors contributed equally to this work.

Affiliations

  1. Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, UK

    • Andrew S. Doré
    • , Krzysztof Okrasa
    • , Jayesh C. Patel
    • , Maria Serrano-Vega
    • , Kirstie Bennett
    • , Robert M. Cooke
    • , James C. Errey
    • , Ali Jazayeri
    • , Samir Khan
    • , Ben Tehan
    • , Malcolm Weir
    • , Giselle R. Wiggin
    •  & Fiona H. Marshall

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Contributions

J.C.P., G.R.W. and S.K. carried out the conformational thermostabilization of the constructs and determined the stability of the StaR in a panel of reagents/additives to aid purification and crystallization. K.B. carried out the pharmacology. A.J. devised the stabilization strategy and designed the T4L fusion matrix. A.J. and J.C.P. carried out functional analyses the mutants. J.C.E. contributed to construct design and purification strategy. M.S.-V. characterized truncation constructs and established procedures for, and carried out expression and purification. K.O. performed expression, purification, LCP crystallization, optimized purification and performed crystallization in LCP for data collection of the final construct. A.S.D. designed crystallization constructs, established the platform/protocols for, and carried out LCP crystallization and designed crystal optimization, harvested crystals, collected and processed X-ray diffraction data, solved and refined the structure, and devised functional mutations. Computational analysis of the structure and modelling was carried out by B.T. and A.S.D. Project management was carried out by A.J., R.M.C., M.W. and F.H.M. The manuscript was prepared by A.S.D., B.T., A.J., R.M.C., K.B. and F.H.M.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Fiona H. Marshall.

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DOI

https://doi.org/10.1038/nature13396

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