Conformational diversity in class C GPCR positive allosteric modulation
Abstract The metabotropic glutamate receptors (mGlus) are class C G protein-coupled receptors (GPCR) that form obligate dimers activated by the major excitatory neurotransmitter L-glutamate. The architecture of mGlu receptor comprises an extracellular Venus-Fly Trap domain (VFT) connected to the tra...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55439-9 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594563161653248 |
|---|---|
| author | Giuseppe Cannone Ludovic Berto Fanny Malhaire Gavin Ferguson Aurelien Fouillen Stéphanie Balor Joan Font-Ingles Amadeu Llebaria Cyril Goudet Abhay Kotecha Vinothkumar K.R. Guillaume Lebon |
| author_facet | Giuseppe Cannone Ludovic Berto Fanny Malhaire Gavin Ferguson Aurelien Fouillen Stéphanie Balor Joan Font-Ingles Amadeu Llebaria Cyril Goudet Abhay Kotecha Vinothkumar K.R. Guillaume Lebon |
| author_sort | Giuseppe Cannone |
| collection | DOAJ |
| description | Abstract The metabotropic glutamate receptors (mGlus) are class C G protein-coupled receptors (GPCR) that form obligate dimers activated by the major excitatory neurotransmitter L-glutamate. The architecture of mGlu receptor comprises an extracellular Venus-Fly Trap domain (VFT) connected to the transmembrane domain (7TM) through a Cysteine-Rich Domain (CRD). The binding of L-glutamate in the VFTs and subsequent conformational change results in the signal being transmitted to the 7TM inducing G protein binding and activation. The mGlu receptors signal transduction can be allosterically potentiated by positive allosteric modulators (PAMs) binding to the 7TMs, which are of therapeutic interest in various neurological disorders. Here, we report the cryoEM structures of metabotropic glutamate receptor 5 (mGlu5) purified with three chemically and pharmacologically distinct PAMs. We find that the PAMs modulate the receptor equilibrium through their different binding modes, revealing how their interactions in the 7TMs impact the mGlu5 receptor conformational landscape and function. In addition, we identified a PAM-free but agonist-bound intermediate state that also reveals interactions mediated by intracellular loop 2. The activation of mGlu5 receptor is a multi-step process in which the binding of the PAMs in the 7TM modulates the equilibrium towards the active state. |
| format | Article |
| id | doaj-art-a14138e27cfe45fbb1ca1c3729dc47e1 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a14138e27cfe45fbb1ca1c3729dc47e12025-01-19T12:32:15ZengNature PortfolioNature Communications2041-17232025-01-0116111710.1038/s41467-024-55439-9Conformational diversity in class C GPCR positive allosteric modulationGiuseppe Cannone0Ludovic Berto1Fanny Malhaire2Gavin Ferguson3Aurelien Fouillen4Stéphanie Balor5Joan Font-Ingles6Amadeu Llebaria7Cyril Goudet8Abhay Kotecha9Vinothkumar K.R.10Guillaume Lebon11MRC Laboratory of Molecular BiologyIGF, Université de Montpellier, CNRS, INSERMIGF, Université de Montpellier, CNRS, INSERMIGF, Université de Montpellier, CNRS, INSERMIGF, Université de Montpellier, CNRS, INSERMMETi, Centre de Biologie Intégrative, Université de Touluse, CNRS, UPSMCS, Laboratory of Medicinal Chemistry & Synthesis, Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26MCS, Laboratory of Medicinal Chemistry & Synthesis, Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26IGF, Université de Montpellier, CNRS, INSERMMaterial and Structure Analysis Division, Thermo Fisher ScientificNational Centre for Biological Sciences, Tata Institute of Fundamental Research, GKVK PostIGF, Université de Montpellier, CNRS, INSERMAbstract The metabotropic glutamate receptors (mGlus) are class C G protein-coupled receptors (GPCR) that form obligate dimers activated by the major excitatory neurotransmitter L-glutamate. The architecture of mGlu receptor comprises an extracellular Venus-Fly Trap domain (VFT) connected to the transmembrane domain (7TM) through a Cysteine-Rich Domain (CRD). The binding of L-glutamate in the VFTs and subsequent conformational change results in the signal being transmitted to the 7TM inducing G protein binding and activation. The mGlu receptors signal transduction can be allosterically potentiated by positive allosteric modulators (PAMs) binding to the 7TMs, which are of therapeutic interest in various neurological disorders. Here, we report the cryoEM structures of metabotropic glutamate receptor 5 (mGlu5) purified with three chemically and pharmacologically distinct PAMs. We find that the PAMs modulate the receptor equilibrium through their different binding modes, revealing how their interactions in the 7TMs impact the mGlu5 receptor conformational landscape and function. In addition, we identified a PAM-free but agonist-bound intermediate state that also reveals interactions mediated by intracellular loop 2. The activation of mGlu5 receptor is a multi-step process in which the binding of the PAMs in the 7TM modulates the equilibrium towards the active state.https://doi.org/10.1038/s41467-024-55439-9 |
| spellingShingle | Giuseppe Cannone Ludovic Berto Fanny Malhaire Gavin Ferguson Aurelien Fouillen Stéphanie Balor Joan Font-Ingles Amadeu Llebaria Cyril Goudet Abhay Kotecha Vinothkumar K.R. Guillaume Lebon Conformational diversity in class C GPCR positive allosteric modulation Nature Communications |
| title | Conformational diversity in class C GPCR positive allosteric modulation |
| title_full | Conformational diversity in class C GPCR positive allosteric modulation |
| title_fullStr | Conformational diversity in class C GPCR positive allosteric modulation |
| title_full_unstemmed | Conformational diversity in class C GPCR positive allosteric modulation |
| title_short | Conformational diversity in class C GPCR positive allosteric modulation |
| title_sort | conformational diversity in class c gpcr positive allosteric modulation |
| url | https://doi.org/10.1038/s41467-024-55439-9 |
| work_keys_str_mv | AT giuseppecannone conformationaldiversityinclasscgpcrpositiveallostericmodulation AT ludovicberto conformationaldiversityinclasscgpcrpositiveallostericmodulation AT fannymalhaire conformationaldiversityinclasscgpcrpositiveallostericmodulation AT gavinferguson conformationaldiversityinclasscgpcrpositiveallostericmodulation AT aurelienfouillen conformationaldiversityinclasscgpcrpositiveallostericmodulation AT stephaniebalor conformationaldiversityinclasscgpcrpositiveallostericmodulation AT joanfontingles conformationaldiversityinclasscgpcrpositiveallostericmodulation AT amadeullebaria conformationaldiversityinclasscgpcrpositiveallostericmodulation AT cyrilgoudet conformationaldiversityinclasscgpcrpositiveallostericmodulation AT abhaykotecha conformationaldiversityinclasscgpcrpositiveallostericmodulation AT vinothkumarkr conformationaldiversityinclasscgpcrpositiveallostericmodulation AT guillaumelebon conformationaldiversityinclasscgpcrpositiveallostericmodulation |