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Interplay of cholesterol, membrane bilayers and the AT1R: A cholesterol consensus motif on AT1R is revealed

Sofia Kiriakidi^1,2, Christos Chatzigiannis³, Christina Papaemmanouil³

¹National and Kapodistrian University of Athens, Department of Chemistry, Athens, Greece.

Computational and Structural Biotechnology Journal

|January 1, 2021

Insights

Cholesterol significantly influences Angiotensin II receptor type 1 (AT1R) function and candesartan binding. This understanding of cholesterol-lipid-AT1R interactions may lead to improved hypertension treatments.

Area of Science:

Cardiovascular Pharmacology
Membrane Biophysics
Computational Chemistry

Background:

Hypertension remains a leading cause of mortality despite available treatments.
Understanding drug-receptor interactions within the membrane environment is crucial for developing effective therapeutics.
The Angiotensin II receptor type 1 (AT1R) is a key target for hypertension medication.

Purpose of the Study:

To investigate the role of cholesterol in the interaction between candesartan and the AT1R.
To elucidate the impact of a cholesterol-rich membrane environment on drug binding mechanisms.
To explore the influence of lipid composition on AT1R function.

Main Methods:

Molecular Dynamics (MD) simulations of AT1R in a DPPC:cholesterol model membrane.
Validation of membrane models using Diffusion Ordered Spectroscopy Nuclear Magnetic Resonance (DOSY NMR) experiments.
Analysis of candesartan diffusion and AT1R interactions within the simulated membrane.

Main Results:

Cholesterol plays a significant role in AT1R function via a Cholesterol Consensus Motif (CCM).
Cholesterol retards the diffusion of candesartan into lipid bilayers.
Cholesterol binding to the CCM may facilitate candesartan's direct approach to the AT1R.

Conclusions:

Cholesterol's influence on AT1R structure and dynamics is critical for drug recognition.
Novel insights into cholesterol-AT1R-drug interplay can guide the development of more effective antihypertensive drugs.
Targeting cholesterol-mediated AT1R modulation presents a potential therapeutic strategy.

Read full analysis

Abstract:

Hypertension, mediated by the Angiotensin II receptor type 1 (AT1R), is still the major cause of premature death despite the discovery of novel therapeutics, highlighting the importance of an in depth understanding of the drug-AT1R recognition mechanisms coupled with the impact of the membrane environment on the interaction of drugs with AT1R. Herein, we examine the interplay of cholesterol-lipid-candesartan and the AT1R using Molecular Dynamics simulations of a model membrane consisting of 60:40 mol%. DPPC:cholesterol, candesartan and the AT1R, mimicking the physiological cholesterol concentration in sarcolemma membranes. The simulations of the model membrane of 60:40 mol%. DPPC:cholesterol were further validated using DOSY NMR experiments. Interestingly, our results suggest a significant role of cholesterol in the AT1R function imposed through a Cholesterol Consensus Motif (CCM) in the receptor, which could be crucial in the drug binding process. Candesartan diffusion towards AT1R through incorporation into lipid bilayers, appears to be retarded by the presence of cholesterol. However, its direct approach towards AT1R may be facilitated through the mobility induced on the N-terminus by the cholesterol binding on the CCM these novel insights could pave the way towards the development of more potent pharmaceutical agents to combat hypertension more effectively.

Keywords:

AT1R CCM Candesartan Cholesterol DOSY DPPC Molecular Dynamics NMR

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