The molecular mechanism of positive allosteric modulation at the dopamine D1 receptor.
Journal
bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187
Informations de publication
Date de publication:
30 Jul 2023
30 Jul 2023
Historique:
medline:
7
8
2023
pubmed:
7
8
2023
entrez:
7
8
2023
Statut:
epublish
Résumé
The dopamine D1 receptor (D1R) is a promising target for treating various psychiatric disorders. While upregulation of D1R activity has shown potential in alleviating motor and cognitive symptoms, orthosteric agonists have limitations, restricting their clinical applications. However, the discovery of several allosteric compounds specifically targeting the D1R, such as LY3154207, has opened new therapeutic avenues. Based on the cryo-EM structures of the D1R, we conducted molecular dynamics simulations to investigate the binding and allosteric mechanisms of LY3154207. Our simulations revealed that LY3154207 preferred the horizontal orientation above intracellular loop 2 (IL2) and stabilized the helical conformation of IL2. Moreover, LY3154207 binding induced subtle yet significant changes in key structural motifs and their neighboring residues. Notably, a cluster of residues centered around the Na
Identifiants
pubmed: 37546785
doi: 10.1101/2023.07.27.550907
pmc: PMC10402154
pii:
doi:
Types de publication
Preprint
Langues
eng
Subventions
Organisme : Intramural NIH HHS
ID : ZIA DA000606
Pays : United States
Commentaires et corrections
Type : UpdateIn
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