Toward Understanding the Impact of Dimerization Interfaces in Angiotensin II Type 1 Receptor
- Ismail Erol*Ismail Erol*E-mail: [email protected] (I.E.).Department of Chemistry, Gebze Technical University, Gebze 41400, Kocaeli, TurkeyComputational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul 34746, TurkeyMore by Ismail Erol
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- Bunyemin CosutBunyemin CosutDepartment of Chemistry, Gebze Technical University, Gebze 41400, Kocaeli, TurkeyMore by Bunyemin Cosut
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- Serdar Durdagi*Serdar Durdagi*E-mail: [email protected] (S.D.).Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine and Neuroscience Program, Graduate School of Health Sciences, Bahcesehir University, Istanbul 34746, TurkeyMore by Serdar Durdagi
Abstract
Angiotensin II type 1 receptor (AT1R) is a prototypical class A G protein-coupled receptor (GPCR) that has an important role in cardiovascular pathologies and blood pressure regulation as well as in the central nervous system. GPCRs may exist and function as monomers; however, they can assemble to form higher order structures, and as a result of oligomerization, their function and signaling profiles can be altered. In the case of AT1R, the classical Gαq/11 pathway is initiated with endogenous agonist angiotensin II binding. A variety of cardiovascular pathologies such as heart failure, diabetic nephropathy, atherosclerosis, and hypertension are associated with this pathway. Recent findings reveal that AT1R can form homodimers and activate the noncanonical (β-arrestin-mediated) pathway. Nevertheless, the exact dimerization interface and atomic details of AT1R homodimerization have not been still elucidated. Here, six different symmetrical dimer interfaces of AT1R are considered, and homodimers were constructed using other published GPCR crystal dimer interfaces as template structures. These AT1R homodimers were then inserted into the model membrane bilayers and subjected to all-atom molecular dynamics simulations. Our simulation results along with the principal component analysis and water pathway analysis suggest four different interfaces as the most plausible: symmetrical transmembrane (TM)1,2,8; TM5; TM4; and TM4,5 AT1R dimer interfaces that consist of one inactive and one active protomer. Moreover, we identified ILE2386.33 as a hub residue in the stabilization of the inactive state of AT1R.
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