title: Water-mediated interactions influence the binding of thapsigargin to sarco/endoplasmic reticulum calcium adenosinetriphosphatase.
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.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Eleonora S
authors.initials: ES
authors.lastname: Paulsen
authors.forename: Jesper
authors.initials: J
authors.lastname: Villadsen
authors.forename: Eleonora
authors.initials: E
authors.lastname: Tenori
authors.forename: Huizhen
authors.initials: H
authors.lastname: Liu
authors.forename: Ditte F
authors.initials: DF
authors.lastname: Bonde
authors.forename: Mette A
authors.initials: MA
authors.lastname: Lie
authors.forename: Maike
authors.initials: M
authors.lastname: Bublitz
authors.forename: Claus
authors.initials: C
authors.lastname: Olesen
authors.forename: Henriette E
authors.initials: HE
authors.lastname: Autzen
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dach
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sehgal
authors.forename: Poul
authors.initials: P
authors.lastname: Nissen
authors.forename: Jesper V
authors.initials: JV
authors.lastname: Møller
authors.forename: Birgit
authors.initials: B
authors.lastname: Schiøtt
authors.forename: S Brøgger
authors.initials: SB
authors.lastname: Christensen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000737:chemistry* / Q000378:metabolism*; D019284:Thapsigargin / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D014867:Water / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D014867:Water; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases