Open AccessElucidation of Mechanism for Ligand Efficacy at Leukotriene B4 Receptor 2 (BLT2)
Author(s) -
Minsup Kim,
Jun Wei,
Dipesh S. Harmalkar,
Ja Il Goo,
Kyeong Lee,
Yongseok Choi,
Jae Hong Kim,
Art E. Cho
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00065
Subject(s) - g protein coupled receptor , drug discovery , ligand (biochemistry) , agonist , mutagenesis , computational biology , chemotaxis , receptor , chemistry , ligand efficiency , drug , mechanism (biology) , stereochemistry , combinatorial chemistry , pharmacology , mutation , biochemistry , biology , philosophy , epistemology , gene
G protein-coupled receptors (GPCRs) have always been important drug targets in the pharmaceutical industry. One major question for the current GPCR drug discovery is how drugs have distinct efficacies at the same GPCR target. Related to this question, we studied how different ligands can have disparate efficacies at Leukotriene B 4 receptor (BLT2). By using molecular modeling studies, we predicted that Tyr271 6.51 located at TM6 of BLT2 performs as a key trigger for its activation and verified the prediction by site-directed mutagenesis, chemotactic motility studies, which included a chemical derivative of agonist CAY10583. We further identified Asn275 6.55 located at TM6 as a weak activation trigger in BLT2 and performed double mutation studies to confirm our computational results. Our results provide strong evidence for the exact mechanism of ligand efficacy at BLT2.