Water-Mediated Interactions Influence the Binding of Thapsigargin to Sarco/Endoplasmic Reticulum Calcium Adenosinetriphosphatase

作者:Paulsen Eleonora S*; Villadsen Jesper; Tenori Eleonora; Liu Huizhen; Bonde Ditte F; Lie Mette A; Bublitz Maike; Olesen Claus; Autzen Henriette E; Dach Ingrid; Sehgal Pankaj; Nissen Poul; Moller Jesper V; Schiott Birgit; Christensen S Brogger
来源:Journal of Medicinal Chemistry, 2013, 56(9): 3609-3619.
DOI:10.1021/jm4001083

摘要

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.

  • 出版日期2013-5-9