Allosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state.
Allosteric Regulation
/ drug effects
Allosteric Site
Amino Acids
/ chemistry
Biphenyl Compounds
/ chemistry
Bridged Bicyclo Compounds
/ chemistry
Bridged Bicyclo Compounds, Heterocyclic
/ chemistry
Catalytic Domain
Cell Membrane
/ drug effects
Cholesterol Esters
/ chemistry
Diosgenin
/ analogs & derivatives
Disaccharides
/ chemistry
Fluorescence Resonance Energy Transfer
Gene Expression
Glucosides
/ chemistry
Glutamic Acid
/ pharmacology
Glycolipids
/ chemistry
HEK293 Cells
Humans
Indans
/ chemistry
Micelles
Octoxynol
/ chemistry
Protein Binding
Protein Conformation
Protein Multimerization
Receptors, Metabotropic Glutamate
/ agonists
Recombinant Proteins
/ chemistry
Single Molecule Imaging
Xanthenes
/ chemistry
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 09 2021
14 09 2021
Historique:
received:
10
02
2021
accepted:
20
08
2021
entrez:
15
9
2021
pubmed:
16
9
2021
medline:
13
10
2021
Statut:
epublish
Résumé
Much hope in drug development comes from the discovery of positive allosteric modulators (PAM) that display target subtype selectivity and act by increasing agonist potency and efficacy. How such compounds can allosterically influence agonist action remains unclear. Metabotropic glutamate receptors (mGlu) are G protein-coupled receptors that represent promising targets for brain diseases, and for which PAMs acting in the transmembrane domain have been developed. Here, we explore the effect of a PAM on the structural dynamics of mGlu2 in optimized detergent micelles using single molecule FRET at submillisecond timescales. We show that glutamate only partially stabilizes the extracellular domains in the active state. Full activation is only observed in the presence of a PAM or the G
Identifiants
pubmed: 34521824
doi: 10.1038/s41467-021-25620-5
pii: 10.1038/s41467-021-25620-5
pmc: PMC8440590
doi:
Substances chimiques
Amino Acids
0
Biphenyl Compounds
0
Bridged Bicyclo Compounds
0
Bridged Bicyclo Compounds, Heterocyclic
0
Cholesterol Esters
0
Disaccharides
0
Glucosides
0
Glycolipids
0
Indans
0
LY 341495
0
LY 379268
0
Micelles
0
Receptors, Metabotropic Glutamate
0
Recombinant Proteins
0
Xanthenes
0
biphenyl-indanone A
0
dodecyl-beta-melibioside
0
metabotropic glutamate receptor 2
0
diosgenin glucoside
14144-06-0
Glutamic Acid
3KX376GY7L
dodecyl maltoside
69227-93-6
Octoxynol
9002-93-1
Diosgenin
K49P2K8WLX
eglumetad
ONU5A67T2S
cholesteryl succinate
T3J4KS4201
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5426Informations de copyright
© 2021. The Author(s).
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