2013•Journal of Medicinal ChemistryOpen access
Water-Mediated Interactions Influence the Binding of Thapsigargin to Sarco/Endoplasmic Reticulum Calcium Adenosinetriphosphatase
Eleonora S. Paulsen, Jesper S. Villadsen, Eleonora Tenori, Huizhen Liu, Ditte F. Bonde, M. Lie, Maike Bublitz, Claus Olesen, Henriette Elisabeth Autzen, Ingrid Dach, Pankaj Sehgal, Poul Nissen, Jesper V. Møller, Birgit Schiøtt, S. Brøgger Christensen
Open full text 24 citations
Abstract
A crystal structure suggests four water molecules are present in the binding cavity of thapsigargin in sarco/endoplasmic reticulum calcium ATPase (SERCA). Computational chemistry indicates that three of these water molecules mediate an extensive hydrogen-bonding network between thapsigargin and the backbone of SERCA. The orientation of the thapsigargin molecule in SERCA is crucially dependent on these interactions. The hypothesis has been verified by measuring the affinity of newly synthesized model compounds, which are prevented from participating in such water-mediated interactions as hydrogen-bond donors.