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

Eleonora S. Paulsen, Jesper Villadsen, Eleonora Tenori, Huizhen Liu, Ditte F. Bonde, Mette A. Lie, Maike Bublitz, Claus Olesen, Henriette E. Autzen, Ingrid Dach, Pankaj Sehgal, Poul Nissen, Jesper V. Møller, Birgit Schiøtt, S. Brøgger Christensen

Research output: Contribution to journalJournal articleResearchpeer-review


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. © 2013 American Chemical Society.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Issue number9
Pages (from-to)3609-3619
Publication statusPublished - 2013


  • Molecular Medicine
  • Drug Discovery
  • sarcoplasmic reticulum calcium transporting adenosine triphosphatase
  • thapsigargin
  • water
  • article
  • binding affinity
  • chemical binding
  • chemical interaction
  • crystal structure
  • hydrogen bond
  • synthesis
  • Antineoplastic Agents
  • Hydrogen Bonding
  • Ligands
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Thapsigargin
  • Water


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