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

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  • Eleonora S Paulsen, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  • Jesper Villadsen, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  • Eleonora Tenori, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  • Huizhen Liu, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  • Ditte Fast Bonde, Denmark
  • Mette Alstrup Lie
  • ,
  • Maike Bublitz, Denmark
  • Claus Olesen
  • Henriette Elisabeth Autzen
  • Ingrid Dach, Denmark
  • Pankaj Sehgal
  • Poul Nissen
  • Jesper Vuust Møller
  • Birgit Schiøtt
  • SB 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
Issue9
Pages (from-to)3609-3619
Number of pages9
ISSN0022-2623
DOIs
Publication statusPublished - Apr 2013

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