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Open AccessArticle

Structural Changes of Sarco/Endoplasmic Reticulum Ca2+-ATPase Induced by Rutin Arachidonate: A Molecular Dynamics Study

1
Department of Natural Sciences, Eugenio María de Hostos Community College of The City University of New York, 500 Grand Concourse, Bronx, New York, NY 10451, USA
2
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
3
Center of Experimental Medicine of Slovak Academy of Sciences, Institute of Experimental Pharmacology and Toxicology, Department of Biochemical Pharmacology, Dubravska cesta 9, 841 04 Bratislava, Slovakia
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(2), 214; https://doi.org/10.3390/biom10020214
Received: 8 December 2019 / Revised: 15 January 2020 / Accepted: 28 January 2020 / Published: 1 February 2020
Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) maintains the level of calcium concentration in cells by pumping calcium ions from the cytoplasm to the lumen while undergoing substantial conformational changes, which can be stabilized or prevented by various compounds. Here we attempted to clarify the molecular mechanism of action of new inhibitor rutin arachidonate, one of the series of the acylated rutin derivatives. We performed molecular dynamics simulations of SERCA1a protein bound to rutin arachidonate positioned in a pure dipalmitoylphosphatidylcholine bilayer membrane. Our study predicted the molecular basis for the binding of rutin arachidonate towards SERCA1a in the vicinity of the binding site of calcium ions and near the location of the well-known inhibitor thapsigargin. The stable hydrogen bond between Glu771 and rutin arachidonate plays a key role in the binding. SERCA1a is kept in the E2 conformation preventing the formation of important salt bridges between the side chains of several residues, primarily Glu90 and Lys297. All in all, the structural changes induced by the binding of rutin arachidonate to SERCA1a may shift proton balance near the titrable residues Glu771 and Glu309 into neutral species, hence preventing the binding of calcium ions to the transmembrane binding sites and thus affecting calcium homeostasis. Our results could lead towards the design of new types of inhibitors, potential drug candidates for cancer treatment, which could be anchored to the transmembrane region of SERCA1a by a lipophilic fatty acid group. View Full-Text
Keywords: rutin derivatives; SERCA1a; inhibition; molecular dynamics; calcium transport; proton transport rutin derivatives; SERCA1a; inhibition; molecular dynamics; calcium transport; proton transport
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Rodríguez, Y.; Májeková, M. Structural Changes of Sarco/Endoplasmic Reticulum Ca2+-ATPase Induced by Rutin Arachidonate: A Molecular Dynamics Study. Biomolecules 2020, 10, 214.

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