Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain

DOI: 10.1038/nature13396
PMID: 25042998

Authors: Andrew Dore (Heptares Therapeutics Ltd) , Krzysztof Okrasa (Heptares Therapeutics Ltd) , Jayesh C. Patel (Heptares Therapeutics Ltd) , Maria Serrano-Vega (Heptares Therapeutics Ltd) , Kirstie Bennett (Heptares Therapeutics Ltd) , Robert M. Cooke (Heptares Therapeutics Ltd) , James C. Errey (Heptares Therapeutics Ltd) , Ali Jazayeri (Heptares Therapeutics Ltd) , Samir Khan (Heptares Therapeutics Ltd) , Ben Tehan (Heptares Therapeutics Ltd) , Malcolm Weir (Heptares Therapeutics Ltd) , Giselle R. Wiggin (Heptares Therapeutics Ltd) , Fiona H. Marshall (Heptares Therapeutics Ltd)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature , VOL 511 (7511) , PAGES 557 - 562

State: Published (Approved)
Published: July 2014
Diamond Proposal Number(s): 5999

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.

Journal Keywords: Binding; Crystallography; X-Ray; HEK293; Humans; Models; Molecular; Protein; Tertiary; Receptor; Metabotropic; Rhodopsin

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 26/03/2015 15:09

Discipline Tags:

Health & Wellbeing Neurology Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)