Molecular determinants of thapsigargin binding by SERCA Ca2+-ATPase: a computational docking study

Proteins
Stefan Paula, William James Ball

Abstract

Thapsigargin (TG) is a potent and commonly used inhibitor of the ion transport activity of sarco/endoplasmic reticulum Ca2+-ATPases (SERCA). Based on the recently published crystal structures of rabbit muscle SERCA1a in the Ca2+/E1 (E1) and TG/E2 (E2) conformations, we performed computational docking studies to characterize the molecular interactions that govern binding of TG and TG-analogs by the enzyme. Using the program GOLD (genetic optimization for ligand docking) in combination with the scoring function ChemScore, TG was docked into the binding site of the E1 and E2 conformations of SERCA1a. The docking results revealed a consensus ligand-binding mode consistent with the crystal structure and showed that hydrophobic interactions are the primary driving force of TG binding by SERCA. Moreover, it was shown that the conformational changes accompanying the E2 to E1 transition in the enzyme likely displace TG from its favored orientation in the binding site, thereby substantially reducing its binding affinity. This finding illustrates on the molecular level how TG may exert its inhibitory effect in binding tightly to the E2 form and preventing it from converting into its E1 form, a requirement for catalytic function. We also d...Continue Reading

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Citations

Mar 17, 2010·Investigational New Drugs·Steven HutchensDanyelle M Townsend
Oct 22, 2013·Biophysical Journal·Sandeep PallikkuthSeth L Robia
Aug 16, 2012·Physical Chemistry Chemical Physics : PCCP·Emma S E Eriksson, Leif A Eriksson
Sep 11, 2019·Beilstein Journal of Organic Chemistry·Silvie RimpelováTomáš Ruml
Mar 27, 2021·Mechanisms of Ageing and Development·Paloma García-CasasJavier Alvarez
Apr 12, 2013·Journal of Medicinal Chemistry·Eleonora S PaulsenS Brøgger Christensen

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