Water-mediated interactions influence the binding of thapsigargin to sarco/endoplasmic reticulum calcium adenosinetriphosphatase

Research output: Contribution to journalJournal articleResearchpeer-review

Eleonora Sandholdt Paulsen, Jesper Villadsen, Eleonora Tenori, Huizhen Liu, Ditte Fast Bonde, Mette Alstrup Lie, Maike Bublitz, Claus Linding Olesen, Henriette Elizabeth Autzen, Ingrid Dach, Pankaj Sehgal, Poul Nissen, Jesper Møller, Birgit Schiøtt, S Brøgger Christensen

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.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume56
Issue number9
Pages (from-to)3609-19
Number of pages11
DOIs
Publication statusPublished - 9 May 2013

ID: 45874326