G-protein Activation by a Metabotropic Glutamate Receptor

Overview

Journal Nature

Specialty Science

Date 2021 Jul 1

PMID 34194039

Citations 67

Authors

Alpay B Seven

Ximena Barros-Alvarez

Marine de Lapeyriere

Makaia M Papasergi-Scott

Michael J Robertson

Chensong Zhang

Robert M Nwokonko

Yang Gao

Justin G Meyerowitz

Jean-Philippe Rocher

Dominik Schelshorn

Brian K Kobilka

Jesper M Mathiesen

Georgios Skiniotis

Affiliations

Soon will be listed here.

Abstract

Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism. Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric G. Upon activation of the extracellular domain, the two transmembrane domains undergo extensive rearrangement in relative orientation to establish an asymmetric TM6-TM6 interface that promotes conformational changes in the cytoplasmic domain of one protomer. Nucleotide-bound G can be observed pre-coupled to inactive mGlu2, but its transition to the nucleotide-free form seems to depend on establishing the active-state TM6-TM6 interface. In contrast to family A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6 but is facilitated through the coordination of intracellular loops 2 and 3, as well as a critical contribution from the C terminus of the receptor. The findings highlight the synergy of global and local conformational transitions to facilitate a new mode of G-protein activation.

Citing Articles

Molecular basis of β-arrestin coupling to the metabotropic glutamate receptor mGlu3.

Wen T, Du M, Lu Y, Jia N, Lu X, Liu N Nat Chem Biol. 2025; .

PMID: 40050438 DOI: 10.1038/s41589-025-01858-8.

Inosine-5'-monophosphate interacts with the TAS1R3 subunit to enhance sweet taste detection.

Belloir C, Moitrier L, Karolkowski A, Poirier N, Neiers F, Briand L Food Chem (Oxf). 2025; 10:100246.

PMID: 40034539 PMC: 11872639. DOI: 10.1016/j.fochms.2025.100246.

Conformational diversity in class C GPCR positive allosteric modulation.

Cannone G, Berto L, Malhaire F, Ferguson G, Fouillen A, Balor S Nat Commun. 2025; 16(1):619.

PMID: 39805839 PMC: 11730304. DOI: 10.1038/s41467-024-55439-9.

Structure of an LGR dimer - an evolutionary predecessor of glycoprotein hormone receptors.

Gong Z, Chen S, Fu Z, Kloss B, Wang C, Clarke O bioRxiv. 2025; .

PMID: 39803540 PMC: 11722252. DOI: 10.1101/2024.12.31.630923.

Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery.

Conflitti P, Lyman E, Sansom M, Hildebrand P, Gutierrez-de-Teran H, Carloni P Nat Rev Drug Discov. 2025; .

PMID: 39747671 DOI: 10.1038/s41573-024-01083-3.

References

Koehl A, Hu H, Feng D, Sun B, Zhang Y, Robertson M . Structural insights into the activation of metabotropic glutamate receptors. Nature. 2019; 566(7742):79-84. PMC: 6709600. DOI: 10.1038/s41586-019-0881-4. View

Attwood T, Findlay J . Fingerprinting G-protein-coupled receptors. Protein Eng. 1994; 7(2):195-203. DOI: 10.1093/protein/7.2.195. View

Weis W, Kobilka B . The Molecular Basis of G Protein-Coupled Receptor Activation. Annu Rev Biochem. 2018; 87:897-919. PMC: 6535337. DOI: 10.1146/annurev-biochem-060614-033910. View

Niswender C, Conn P . Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol. 2010; 50:295-322. PMC: 2904507. DOI: 10.1146/annurev.pharmtox.011008.145533. View

Conn P, Lindsley C, Jones C . Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharmacol Sci. 2008; 30(1):25-31. PMC: 2907735. DOI: 10.1016/j.tips.2008.10.006. View

Chappell M, Li R, Smith S, Dressman B, Tromiczak E, Tripp A . Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like.... J Med Chem. 2016; 59(24):10974-10993. DOI: 10.1021/acs.jmedchem.6b01119. View

Monn J, Prieto L, Taboada L, Hao J, Reinhard M, Henry S . Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid.... J Med Chem. 2015; 58(18):7526-48. DOI: 10.1021/acs.jmedchem.5b01124. View

Galici R, Echemendia N, Rodriguez A, Conn P . A selective allosteric potentiator of metabotropic glutamate (mGlu) 2 receptors has effects similar to an orthosteric mGlu2/3 receptor agonist in mouse models predictive of antipsychotic activity. J Pharmacol Exp Ther. 2005; 315(3):1181-7. DOI: 10.1124/jpet.105.091074. View

Kingston A, Ornstein P, Wright R, Johnson B, Mayne N, Burnett J . LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology. 1998; 37(1):1-12. DOI: 10.1016/s0028-3908(97)00191-3. View

10.

Bollinger K, Felts A, Brassard C, Engers J, Rodriguez A, Weiner R . Design and Synthesis of mGlu NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core. ACS Med Chem Lett. 2017; 8(9):919-924. PMC: 5601377. DOI: 10.1021/acsmedchemlett.7b00279. View

11.

Papasergi-Scott M, Robertson M, Seven A, Panova O, Mathiesen J, Skiniotis G . Structures of metabotropic GABA receptor. Nature. 2020; 584(7820):310-314. PMC: 7429364. DOI: 10.1038/s41586-020-2469-4. View

12.

Farinha A, Lavreysen H, Peeters L, Russo B, Masure S, Trabanco A . Molecular determinants of positive allosteric modulation of the human metabotropic glutamate receptor 2. Br J Pharmacol. 2015; 172(9):2383-96. PMC: 4403101. DOI: 10.1111/bph.13065. View

13.

Lundstrom L, Bissantz C, Beck J, Wettstein J, Woltering T, Wichmann J . Structural determinants of allosteric antagonism at metabotropic glutamate receptor 2: mechanistic studies with new potent negative allosteric modulators. Br J Pharmacol. 2011; 164(2b):521-37. PMC: 3188907. DOI: 10.1111/j.1476-5381.2011.01409.x. View

14.

Christopher J, Aves S, Bennett K, Dore A, Errey J, Jazayeri A . Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile). J Med Chem. 2015; 58(16):6653-64. DOI: 10.1021/acs.jmedchem.5b00892. View

15.

Xue L, Rovira X, Scholler P, Zhao H, Liu J, Pin J . Major ligand-induced rearrangement of the heptahelical domain interface in a GPCR dimer. Nat Chem Biol. 2014; 11(2):134-40. DOI: 10.1038/nchembio.1711. View

16.

Thibado J, Tano J, Lee J, Salas-Estrada L, Provasi D, Strauss A . Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors. Elife. 2021; 10. PMC: 8102066. DOI: 10.7554/eLife.67027. View

17.

Goudet C, Gaven F, Kniazeff J, Vol C, Liu J, Cohen-Gonsaud M . Heptahelical domain of metabotropic glutamate receptor 5 behaves like rhodopsin-like receptors. Proc Natl Acad Sci U S A. 2003; 101(1):378-83. PMC: 314193. DOI: 10.1073/pnas.0304699101. View

18.

Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debinski A, Filipek S . Action of molecular switches in GPCRs--theoretical and experimental studies. Curr Med Chem. 2012; 19(8):1090-109. PMC: 3343417. DOI: 10.2174/092986712799320556. View

19.

Maeda S, Qu Q, Robertson M, Skiniotis G, Kobilka B . Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes. Science. 2019; 364(6440):552-557. PMC: 7034192. DOI: 10.1126/science.aaw5188. View

20.

Thal D, Sun B, Feng D, Nawaratne V, Leach K, Felder C . Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. Nature. 2016; 531(7594):335-40. PMC: 4915387. DOI: 10.1038/nature17188. View