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1 Department of Chemistry, Technical University of Denmark 2 University of Copenhagen 3 Organic Chemistry, Department of Chemistry, Technical University of Denmark 4 Aarhus University 5 Danish National Research Foundation
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.
Journal of Medicinal Chemistry, 2013, Vol 56, Issue 9, p. 3609-3619
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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