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

Research output: Contribution to journal › Journal article › Research › peer-review

23 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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10.1021/jm4001083

Cite this

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

Water-mediated interactions influence the binding of thapsigargin to sarco/endoplasmic reticulum calcium adenosinetriphosphatase. / Paulsen, Eleonora Sandholdt; Villadsen, Jesper; Tenori, Eleonora; Liu, Huizhen; Bonde, Ditte Fast; Lie, Mette Alstrup; Bublitz, Maike; Olesen, Claus Linding; Autzen, Henriette Elizabeth; Dach, Ingrid; Sehgal, Pankaj; Nissen, Poul; Møller, Jesper; Schiøtt, Birgit; Christensen, S Brøgger.

In: Journal of Medicinal Chemistry, Vol. 56, No. 9, 09.05.2013, p. 3609-19.

Research output: Contribution to journal › Journal article › Research › peer-review

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

Paulsen, Eleonora Sandholdt ; Villadsen, Jesper ; Tenori, Eleonora ; Liu, Huizhen ; Bonde, Ditte Fast ; Lie, Mette Alstrup ; Bublitz, Maike ; Olesen, Claus Linding ; Autzen, Henriette Elizabeth ; Dach, Ingrid ; Sehgal, Pankaj ; Nissen, Poul ; Møller, Jesper ; Schiøtt, Birgit ; Christensen, S Brøgger. / Water-mediated interactions influence the binding of thapsigargin to sarco/endoplasmic reticulum calcium adenosinetriphosphatase. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 9. pp. 3609-19.

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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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AU - Bonde, Ditte Fast

AU - Lie, Mette Alstrup

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AU - Olesen, Claus Linding

AU - Autzen, Henriette Elizabeth

AU - Dach, Ingrid

AU - Sehgal, Pankaj

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AU - Møller, Jesper

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AU - Christensen, S Brøgger

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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.

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