G-protein activation by a metabotropic glutamate receptor

Seven, Alpay B.; Barros-Álvarez, Ximena; Lapeyrière, Marine de; Papasergi-Scott, Makaía M.; Robertson, Michael J.; Zhang, Chen-Song; Nwokonko, Robert M.; Gao, Yang; Meyerowitz, Justin; Rocher, Jean‐Philippe; Schelshorn, Dominik W.; Kobilka, Brian K.; Mathiesen, Jesper Mosolff; Skiniotis, Georgios

doi:10.1038/s41586-021-03680-3

Cited by 103 publications

(135 citation statements)

References 57 publications

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“…9q ). Conformation of the three ICLs of GPR158 bound to the RGS7 are similar to those of Gi-bound GABA B , mGluR2, and mGluR4 34 , 36 , 45 , 46 (Fig. 5c ).…”

Section: Resultsmentioning

confidence: 64%

“…The GPR158–RGS7 interaction is much more extensive than other reported GPCR-RGS interactions. The GPR158–RGS7–Gβ5 complex structures suggest that direct coupling of GPR158 with G protein via ICLs similar to those observed in GABA B , mGluR2, mGluR4, and Ste2 is unlikely in the presence of RGS7–Gβ5 complex because the RGS7–Gβ5 complex and G protein would collide each other 36 , 45 , 46 , 56 (Supplementary Fig. 11c ).…”

Section: Discussionmentioning

confidence: 87%

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Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5

et al. 2021

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GPR158, a class C orphan GPCR, functions in cognition, stress-induced mood control, and synaptic development. Among class C GPCRs, GPR158 is unique as it lacks a Venus flytrap-fold ligand-binding domain and terminates Gαi/o protein signaling through the RGS7-Gβ5 heterodimer. Here, we report the cryo-EM structures of GPR158 alone and in complex with one or two RGS7-Gβ5 heterodimers. GPR158 dimerizes through Per-Arnt-Sim-fold extracellular and transmembrane (TM) domains connected by an epidermal growth factor-like linker. The TM domain (TMD) reflects both inactive and active states of other class C GPCRs: a compact intracellular TMD, conformations of the two intracellular loops (ICLs) and the TMD interface formed by TM4/5. The ICL2, ICL3, TM3, and first helix of the cytoplasmic coiled-coil provide a platform for the DHEX domain of one RGS7 and the second helix recruits another RGS7. The unique features of the RGS7-binding site underlie the selectivity of GPR158 for RGS7.

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“…9q ). Conformation of the three ICLs of GPR158 bound to the RGS7 are similar to those of Gi-bound GABA B , mGluR2, and mGluR4 34 , 36 , 45 , 46 (Fig. 5c ).…”

Section: Resultsmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 87%

Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5

et al. 2021

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“…In this scenario, key regions in the GB2 TMD, also called microswitches, should play a key role to stabilize the active state, as well as reported in class A GPCRs ( Zhou et al, 2019 ). These microswitches regions remain largely unknown in the class C GPCRs due to the lack of high-resolution structures in the active and inactive states ( Gao et al, 2021 ; Koehl et al, 2019 ; Lin et al, 2021 ; Mao et al, 2020 ; Seven et al, 2021 ; Shaye et al, 2020 ; Shen et al, 2021 ). We explored a region underneath the phospholipid cavity, named ‘deep region’ in this study, that corresponds to the Na + binding pocket in most class A GPCRs ( Zarzycka et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

“…The binding mode of PAMs in the GABA B is novel within the class C GPCRs where all allosteric compounds that bind in the TMD are found in the ancestral TMD binding pocket, as revealed by the structures of mGlu1 ( Wu et al, 2014 ), mGlu2 ( Lin et al, 2021 ; Seven et al, 2021 ), mGlu5 ( Doré et al, 2014 ), and the calcium sensing receptor CaSR ( Gao et al, 2021 ) receptors in complex with allosteric modulators. Similar conclusions were reached for PAMs and NAMs from structure–activity and modeling studies of mGlu ( Bennett et al, 2020 ; Lundström et al, 2017 ; Pérez-Benito et al, 2017 ; Rovira et al, 2015 ) and other class C GPCRs ( Leach and Gregory, 2017 ; Leach et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface

Liu

Fan

Rovira

et al. 2021

eLife

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G protein-coupled receptors (GPCRs) are among the most promising drug targets. They often form homo- and heterodimers with allosteric cross-talk between receptor entities, which contributes to fine tuning of transmembrane signaling. Specifically controlling the activity of GPCR dimers with ligands is a good approach to clarify their physiological roles and to validate them as drug targets. Here, we examined the mode of action of positive allosteric modulators (PAMs) that bind at the interface of the transmembrane domains of the heterodimeric GABAB receptor. Our site-directed mutagenesis results show that mutations of this interface impact the function of the three PAM tested. The data support the inference that they act at the active interface between both transmembrane domains, the binding site involving residues of the TM6s of the GABAB1 and the GABAB2 subunit. Importantly, the agonist activity of these PAMs involves a key region in the central core of the GABAB2 transmembrane domain, which also controls the constitutive activity of the GABAB receptor. This region corresponds to the sodium ion binding site in class A GPCRs that controls the basal state of the receptors. Overall, these data reveal the possibility of developing allosteric compounds able to specifically modulate the activity of GPCR homo- and heterodimers by acting at their transmembrane interface.

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“…The G i heterotrimer in the latter structure had a more rigid nucleotide-binding domain and the receptor adopted features of both active and inactive states, suggesting this conformation was on the activation pathway to form the non-canonical conformation. Differentially populated conformations have also been described for the mGluA2 structure [ 65 ].…”

Section: Access To Conformational Dynamics Of Structuresmentioning

confidence: 99%

Structure determination of GPCRs: cryo-EM compared with X-ray crystallography

García-Nafría

Tate

2021

Biochemical Society Transactions

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G protein-coupled receptors (GPCRs) are the largest single family of cell surface receptors encoded by the human genome and they play pivotal roles in co-ordinating cellular systems throughout the human body, making them ideal drug targets. Structural biology has played a key role in defining how receptors are activated and signal through G proteins and β-arrestins. The application of structure-based drug design (SBDD) is now yielding novel compounds targeting GPCRs. There is thus significant interest from both academia and the pharmaceutical industry in the structural biology of GPCRs as currently only about one quarter of human non-odorant receptors have had their structure determined. Initially, all the structures were determined by X-ray crystallography, but recent advances in electron cryo-microscopy (cryo-EM) now make GPCRs tractable targets for single-particle cryo-EM with comparable resolution to X-ray crystallography. So far this year, 78% of the 99 GPCR structures deposited in the PDB (Jan–Jul 2021) were determined by cryo-EM. Cryo-EM has also opened up new possibilities in GPCR structural biology, such as determining structures of GPCRs embedded in a lipid nanodisc and multiple GPCR conformations from a single preparation. However, X-ray crystallography still has a number of advantages, particularly in the speed of determining many structures of the same receptor bound to different ligands, an essential prerequisite for effective SBDD. We will discuss the relative merits of cryo-EM and X-ray crystallography for the structure determination of GPCRs and the future potential of both techniques.

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G-protein activation by a metabotropic glutamate receptor

Cited by 103 publications

References 57 publications

Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5

Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5

Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface

Structure determination of GPCRs: cryo-EM compared with X-ray crystallography

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