Abstract
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.
Highlights
Calcium signaling plays an important role in many physiological processes, such as muscle contraction, gene expression, cell motility, apoptosis, and insulin secretion [1,2,3,4]
It is known that the 3w5c model is a good starting point for the MD simulation of sarco/endoplasmic reticulum Ca2+-ATPase 1a (SERCA1a) basic properties in the E2 state due to its high resolution of 2.5 Å [39]
All these justify the use of the calculated docked pose of RA in the SERCA1a 3w5c model as the starting geometry for the MD simulation
Summary
Calcium signaling plays an important role in many physiological processes, such as muscle contraction, gene expression, cell motility, apoptosis, and insulin secretion [1,2,3,4]. SERCA is a member of P-type ATPases family, together with Na+/K+-ATPase, H+-ATPase, and H+/K+-ATPase It occurs in several isoforms including: SERCA1—located in the sarcoplasmic or endoplasmic reticula of fast-twitch skeletal muscle cells and plays a key role in muscle contraction. We found the work by Sonntag et al, 2011 [34] where the SERCA1a-lipid interactions were analyzed using MD simulations They found that SERCA1a adapts to different hydrophobic thickness membranes by inducing local deformations in the lipid bilayers and by undergoing small rearrangements of the amino-acid side chains and helix tilts. Another MD simulation study aimed at examining the effects of nonannular lipid binding on the stability of the calcium pump SERCA1a has been conducted [35]. A great deal of attention has been paid to the interaction of SERCA1a with its endogenous modulators phospholamban [36,37] anBdiosmaorlcecoulliepsi2n02[03,81]0., 2O14ther MD simulation studies have dealt with the protonation and proton trans4feorf 20 in SERCA1a [39,40,41]
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