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

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

doi:10.1021/jm4001083

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

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

Department of Drug Design and Pharmacology

22 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	9
Pages (from-to)	3609-19
Number of pages	11
DOIs	https://doi.org/10.1021/jm4001083
Publication status	Published - 9 May 2013

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Paulsen, E. S., Villadsen, J., Tenori, E., Liu, H., Bonde, D. F., Lie, M. A., Bublitz, M., Olesen, C. L., Autzen, H. E., Dach, I., Sehgal, P., Nissen, P., Møller, J., Schiøtt, B., & Christensen, S. B. (2013). Water-mediated interactions influence the binding of thapsigargin to sarco/endoplasmic reticulum calcium adenosinetriphosphatase. Journal of Medicinal Chemistry, 56(9), 3609-19. https://doi.org/10.1021/jm4001083

Paulsen, ES, Villadsen, J, Tenori, E, Liu, H, Bonde, DF, Lie, MA, Bublitz, M, Olesen, CL, Autzen, HE, Dach, I, Sehgal, P, Nissen, P, Møller, J, Schiøtt, B & Christensen, SB 2013, 'Water-mediated interactions influence the binding of thapsigargin to sarco/endoplasmic reticulum calcium adenosinetriphosphatase', Journal of Medicinal Chemistry, vol. 56, no. 9, pp. 3609-19. https://doi.org/10.1021/jm4001083

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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.",

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year = "2013",

month = may,

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doi = "10.1021/jm4001083",

language = "English",

volume = "56",

pages = "3609--19",

journal = "Journal of Medicinal Chemistry",

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T1 - Water-mediated interactions influence the binding of thapsigargin to sarco/endoplasmic reticulum calcium adenosinetriphosphatase

AU - Paulsen, Eleonora Sandholdt

AU - Villadsen, Jesper

AU - Tenori, Eleonora

AU - Liu, Huizhen

AU - Bonde, Ditte Fast

AU - Lie, Mette Alstrup

AU - Bublitz, Maike

AU - Olesen, Claus Linding

AU - Autzen, Henriette Elizabeth

AU - Dach, Ingrid

AU - Sehgal, Pankaj

AU - Nissen, Poul

AU - Møller, Jesper

AU - Schiøtt, Birgit

AU - Christensen, S Brøgger

PY - 2013/5/9

Y1 - 2013/5/9

N2 - 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.

AB - 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.

U2 - 10.1021/jm4001083

DO - 10.1021/jm4001083

M3 - Journal article

C2 - 23574308

SN - 1520-4804

VL - 56

SP - 3609

EP - 3619

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 9

ER -

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

Abstract

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