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Trans and Cis Conformations of the Antihypertensive Drug Valsartan Respectively Lock the Inactive and Active-like States of Angiotensin II Type 1 Receptor: A Molecular Dynamics Study.

Abstract：

:Angiotensin II type 1 receptor (AT1R) is the principal regulator of blood pressure in humans. The overactivation of AT1R by the stimulation of angiotensin II would result in high blood pressure. To prevent hypertension, nonpeptide "sartan" drugs, such as valsartan (VST), have been developed to competitively block the access of angiotensin II to the receptor. Nuclear magnetic resonance spectroscopy and molecular modeling studies have identified that VST in solution and in lipid micelles (a mimic membrane environment) has two distinct trans/cis conformations (VSTtrans/VSTcis) that can be transformed into each other through the isomerization of the amide bond. To date, it is still not known whether the two conformations of VST can affect the binding of AT1R with VST. To this end, the binding of AT1R with VSTtrans or VSTcis was modeled based on the recently determined crystal structures of AT1R. Molecular dynamics simulations were then performed to study the structural and dynamical differences of AT1R caused by the two conformations of VST. Simulation results show that AT1R with VSTtrans has higher structural and dynamical stabilities compared to that with VSTcis. Binding energy analysis indicates that AT1R bind more strongly with VSTtrans, and the energy difference mainly results from the contribution of van der Waals and nonpolar interactions. Detailed analyses reveal that unlike AT1R with VSTtrans, AT1R with VSTcis displays an activate-like state, which is characterized by a small outward movement of transmembrane helix 6. Due to the altered interaction with the butyl group of VST, residue Tyr87 undergoes a conformational change that causes a contraction of the pocket for VST binding. The rearrangement of AT1R is then propagated to the intracellular side of the receptor through the conformational change of residue Trp253 (the toggle switch), which results in an expansion of the pocket for G protein binding and the breakage of the hydrogen bond containing the conserved residue Arg126. These data provide insights into the activation mechanism of AT1R caused by the binding of VSTcis, which may help to design a new drug to inhibit AT1R and prevent high blood pressure.

journal_name

J Chem Inf Model

journal_title

Journal of chemical information and modeling

authors

Wang L,Yan F

doi

10.1021/acs.jcim.8b00364

subject

Has Abstract

pub_date

2018-10-22 00:00:00

pages

2123-2130

issue

eissn

1549-9596

issn

1549-960X

journal_volume

pub_type

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Trans and Cis Conformations of the Antihypertensive Drug Valsartan Respectively Lock the Inactive and Active-like States of Angiotensin II Type 1 Receptor: A Molecular Dynamics Study.