Deciphering the Activation Mechanism and Internal Signaling Pathways of Dopamine Receptor D1 bound with Various...

Dopamine receptors (DRs), belonging to class A G-protein coupled receptors (GPCRs), are comprised of D1-like and D2-like subtypes. The dopamine receptor D1 (D1DR), the most abundant DR in the human central nervous system, is involved in various neurological functions and is a promising target for psychiatric disorders. This study investigates the activation mechanisms, hydrogen bond network, and signaling pathway of D1DR interacting with different functional ligands using molecular dynamics simulations based on the cryo-EM structure. Our simulations revealed that partial agonist-bound systems exhibited only slight activation conformations compared to full agonist-bound systems. Notably, these conformational changes blocked the G-protein binding pocket, preventing coupling with the stimulatory G-protein (Gs). Additionally, we identified potential pathways from the orthosteric ligand binding site to the G-protein binding pocket. These findings provide crucial insights into D1DR function and ligand interactions, potentially informing the development of novel therapeutic strategies for D1DR-related neuropsychiatric disorders. The study advances our understanding of D1DR activation mechanisms and signaling pathways, which may contribute to the design of more selective and efficacious D1DRtargeted drugs.