Transmembrane Domains IV, V, VI, and VII Contribute to Human Angiotensin II Type 1 Receptor Homomer Formation

Abstract

From schizophrenia to asthma, GPCRs have an important role in drug therapy. This work focuses on the AT1R; a GPCR with widespread use in the treatment of cardiovascular disease. Specifically, this work examines the structural aspects of AT1R dimerization, which has been shown to have profound effects on receptor pharmacology. We hypothesized that AT1R homomer formation is driven by hydrophobic amino acids that are exposed to the phospholipid bilayer. A three-dimensional homology model of the AT1R was developed and subsequently validated by a recently published crystal structure. This model was used to guide site-directed mutagenesis, and BRET was used to characterize receptor mutants. The data presented herein demonstrates that hydrophobic amino acids within TMs III, IV, V, VI, and VII contribute to AT1R-AT1R affinity. These findings provide the first glimpse at AT1R homomer structure using GOMoDo and may provide a foundation for the development of drugs that target AT1R dimers.