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TitleStepwise activation of a metabotropic glutamate receptor.
Journal, issue, pagesNature, Vol. 629, Issue 8013, Page 951-956, Year 2024
Publish dateApr 17, 2024
AuthorsKaavya Krishna Kumar / Haoqing Wang / Chris Habrian / Naomi R Latorraca / Jun Xu / Evan S O'Brien / Chensong Zhang / Elizabeth Montabana / Antoine Koehl / Susan Marqusee / Ehud Y Isacoff / Brian K Kobilka /
PubMed AbstractMetabotropic glutamate receptors belong to a family of G protein-coupled receptors that are obligate dimers and possess a large extracellular ligand-binding domain that is linked via a cysteine-rich ...Metabotropic glutamate receptors belong to a family of G protein-coupled receptors that are obligate dimers and possess a large extracellular ligand-binding domain that is linked via a cysteine-rich domain to their 7-transmembrane domain. Upon activation, these receptors undergo a large conformational change to transmit the ligand binding signal from the extracellular ligand-binding domain to the G protein-coupling 7-transmembrane domain. In this manuscript, we propose a model for a sequential, multistep activation mechanism of metabotropic glutamate receptor subtype 5. We present a series of structures in lipid nanodiscs, from inactive to fully active, including agonist-bound intermediate states. Further, using bulk and single-molecule fluorescence imaging, we reveal distinct receptor conformations upon allosteric modulator and G protein binding.
External linksNature / PubMed:38632403 / PubMed Central
MethodsEM (single particle)
Resolution2.89 - 4.65 Å
Structure data

41069

8t6j

EMDB-41069, PDB-8t6j:
CDPPB-bound inactive mGlu5
Method: EM (single particle) / Resolution: 3.5 Å

41092

8t7h

EMDB-41092, PDB-8t7h:
Quis-bound intermediate mGlu5
Method: EM (single particle) / Resolution: 3.3 Å

41099

8t8m

EMDB-41099, PDB-8t8m:
Quis-bound intermediate mGlu5
Method: EM (single particle) / Resolution: 3.0 Å

41139

8tao

EMDB-41139, PDB-8tao:
Quis and CDPPB bound active mGlu5
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-41783: CDPPB bound inactive mGlu5, local refinement on TM region
Method: EM (single particle) / Resolution: 4.0 Å

EMDB-41787: CDPPB bound inactive mGlu5, non-uniform refinement of the whole complex
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-41789: TM region local refinement of CDPPB, QUS bound mGlu5 in complex with Nb43
Method: EM (single particle) / Resolution: 4.46 Å

EMDB-41793: CDDPPB, QUS bound mGlu5 in complex with Nb43, local refinement on the VFT region
Method: EM (single particle) / Resolution: 2.89 Å

EMDB-41804: QUS bound active mGlu5 in complex with Nb43, local refinement on the TM region
Method: EM (single particle) / Resolution: 4.24 Å

EMDB-41807: QUS bounds mGlu5 in complex with Nb43, non uniform refinement on the whole complex
Method: EM (single particle) / Resolution: 3.33 Å

EMDB-41808: QUS bound inactive mGlu5 in complex with Nb43, local refinement on the TM region
Method: EM (single particle) / Resolution: 4.65 Å

Chemicals

ChemComp-YKU:
3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide

ChemComp-QUS:
(S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsSIGNALING PROTEIN / GPCR

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