Unraveling the Molecular Architecture of Mosquito D1-Like Dopamine Receptors: Insights Into Ligand Binding and Structural Dynamics for Insecticide Development.

Abstract

Vector-borne diseases pose a severe threat to human life, contributing significantly to global mortality. Understanding the structure-function relationship of the vector proteins is pivotal for effective insecticide development due to their involvement in drug resistance and disease transmission. This study reports the structural and dynamic features of D1-like dopamine receptors (DARs) in disease-causing mosquito species, such as Aedes aegypti, Culex quinquefasciatus, Anopheles gambiae, and Anopheles stephensi. Through molecular modeling and simulations, we describe the common structural fold of mosquito DARs within the G-protein-coupled receptor family, highlighting the importance of an orthosteric and enlarged binding pocket. The orthosteric binding pocket, resembling a cage-like structure, is situated ~15 Å deep within the protein, with two serine residues forming the roof and an aspartate residue, along with two conserved water molecules (W1 and W2), forming the floor. The side walls are composed of two phenylalanine residues on one side and a valine residue on the other. The antagonist binding site, an enlarged binding pocket (EBP) near the entrance cavity, can accommodate ligands of varying sizes. The binding energy of dopamine is observed to be ~2-3 kcal/mol higher than that of the antagonist molecules amitriptyline, asenapine, and flupenthixol in mosquito DARs. These antagonist molecules bind to EBP, which obstructs dopamine movement toward the active site, thereby inhibiting signal transduction. Our findings elucidate the molecular architecture of the binding pockets and the versatility of DARs in accommodating diverse ligands, providing a foundational framework for future drug and insecticide development.