Analysis of tractable allosteric sites in G protein-coupled receptors.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
16 04 2019
16 04 2019
Historique:
received:
22
01
2019
accepted:
28
03
2019
entrez:
18
4
2019
pubmed:
18
4
2019
medline:
21
10
2020
Statut:
epublish
Résumé
Allosteric modulation of G protein-coupled receptors represent a promising mechanism of pharmacological intervention. Dramatic developments witnessed in the structural biology of membrane proteins continue to reveal that the binding sites of allosteric modulators are widely distributed, including along protein surfaces. Here we restrict consideration to intrahelical and intracellular sites together with allosteric conformational locks, and show that the protein mapping tools FTMap and FTSite identify 83% and 88% of such experimentally confirmed allosteric sites within the three strongest sites found. The methods were also able to find partially hidden allosteric sites that were not fully formed in X-ray structures crystallized in the absence of allosteric ligands. These results confirm that the intrahelical sites capable of binding druglike allosteric modulators are among the strongest ligand recognition sites in a large fraction of GPCRs and suggest that both FTMap and FTSite are useful tools for identifying allosteric sites and to aid in the design of such compounds in a range of GPCR targets.
Identifiants
pubmed: 30992500
doi: 10.1038/s41598-019-42618-8
pii: 10.1038/s41598-019-42618-8
pmc: PMC6467999
doi:
Substances chimiques
Ligands
0
Receptors, G-Protein-Coupled
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6180Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM118078
Pays : United States
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