Cholesterol allosteric modulation of the oxytocin receptor.

Peter W Hildebrand, Alexander Vogel, Georg Kuenze, Peter F Stadler, Jens Meiler, Franziska Reinhardt, Brennica Marlow, Maik Pankonin

Journal: Biophysical journal 2025;124(12):1930-1943

PMID: 40308029

Full Text on Elsevier Science View on PubMed

Abstract

G-protein coupled receptors are critical components in cellular signaling, mediating various physiological responses to external stimuli. Here, we investigate the intricate relationship between cholesterol and the oxytocin receptor (OXTR), focusing on the binding mechanisms and the allosteric cross talk of bound cholesterol to the orthosteric ligand binding pocket. Utilizing molecular docking and molecular dynamics simulations, we identify cholesterol binding sites both on the agonist-bound and antagonist-bound state, which show differing distributions and residence times of the cholesterol molecules. Importantly, both methods converge on several key sites, demonstrating strong predictive overlap. Notably, one such site, and several sites detected by our molecular dynamics approach, also coincide with electron density observed in an experimental cryo-EM map, providing orthogonal validation for computational predictions. Allosteric network analysis uncovers the distinct pathways through which cholesterol may affect ligand-mediated receptor signaling, highlighting the significance of one site on the extracellular leaflet between TM4 and TM5, and two sites on the intracellular leaflet between TM2, TM3, and TM4 and between TM4 and TM5 in transmitting allosteric signals to the orthosteric pocket. These findings provide insights into the impact of cholesterol on OXTR function, emphasizing specific binding sites and signaling paths for further experimental exploration.

Address: Center for Structural Biology, Vanderbilt University, Nashville, Tennessee; Chemical and Physical Biology Program, Vanderbilt University, Nashville, Tennessee; Department of Chemistry, Vanderbilt University, Nashville, Tennessee.; Institute of Medical Physics and Biophysics, Medical Faculty, Leipzig University, Leipzig, Germany.; Institute for Drug Discovery, Medical Faculty, Leipzig University, Leipzig, Germany; Center for Scalable Data Analytics and Artificial Intelligence ScaDS.AI, Leipzig University, Leipzig, Germany; Interdisciplinary Center for Bioinformatics, Leipzig University, Leipzig, Germany.; Bioinformatics Group, Institute of Computer Science, Interdisciplinary Center of Bioinformatics, Leipzig University, Leipzig, Germany.; Center for Scalable Data Analytics and Artificial Intelligence ScaDS.AI, Leipzig University, Leipzig, Germany; Bioinformatics Group, Institute of Computer Science, Interdisciplinary Center of Bioinformatics, Leipzig University, Leipzig, Germany; Max-Planck-Institute for Mathematics in the Sciences, Leipzig, Germany; Institute of Theoretical Chemistry, University of Vienna, Wien, Austria; Facultad de Ciencias, Universidad National de Colombia, Sede Bogota, Colombia; Santa Fe Institute, Santa Fe, New Mexico.; Center for Scalable Data Analytics and Artificial Intelligence ScaDS.AI, Leipzig University, Leipzig, Germany; Institute of Medical Physics and Biophysics, Medical Faculty, Leipzig University, Leipzig, Germany. Electronic address: [email protected].; Center for Structural Biology, Vanderbilt University, Nashville, Tennessee; Institute for Drug Discovery, Medical Faculty, Leipzig University, Leipzig, Germany; Center for Scalable Data Analytics and Artificial Intelligence ScaDS.AI, Leipzig University, Leipzig, Germany; Interdisciplinary Center for Bioinformatics, Leipzig University, Leipzig, Germany; Chemical and Physical Biology Program, Vanderbilt University, Nashville, Tennessee; Department of Chemistry, Vanderbilt University, Nashville, Tennessee. Electronic address: [email protected].

DOI: 10.1016/j.bpj.2025.04.023

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MeSH Terms: Receptors, Oxytocin, Cholesterol, Allosteric Regulation, Molecular Dynamics Simulation, Molecular Docking Simulation, Humans, Binding Sites, Protein Binding, Ligands