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

Eleonora S. Paulsen; Jesper Villadsen; Eleonora Tenori; Huizhen Liu; Ditte F. Bonde; Mette A. Lie; Maike Bublitz; Claus Olesen; Henriette E. Autzen; Ingrid Dach; Pankaj Sehgal; Poul Nissen; Jesper V. 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 S. Paulsen, Jesper Villadsen, Eleonora Tenori, Huizhen Liu, Ditte F. Bonde, Mette A. Lie, Maike Bublitz, Claus Olesen, Henriette E. Autzen, Ingrid Dach, Pankaj Sehgal, Poul Nissen, Jesper V. Møller, Birgit Schiøtt, S. Brøgger Christensen

Department of Chemistry

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

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. © 2013 American Chemical Society.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	9
Pages (from-to)	3609-3619
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm4001083
Publication status	Published - 2013

Keywords

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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Paulsen, E. S., Villadsen, J., Tenori, E., Liu, H., Bonde, D. F., Lie, M. A., Bublitz, M., Olesen, C., Autzen, H. E., Dach, I., Sehgal, P., Nissen, P., Møller, J. V., 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), 3609-3619. https://doi.org/10.1021/jm4001083

Paulsen, Eleonora S. ; Villadsen, Jesper ; Tenori, Eleonora ; Liu, Huizhen ; Bonde, Ditte F. ; Lie, Mette A. ; Bublitz, Maike ; Olesen, Claus ; Autzen, Henriette E. ; Dach, Ingrid ; Sehgal, Pankaj ; Nissen, Poul ; Møller, Jesper V. ; 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. 3609-3619.

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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. {\textcopyright} 2013 American Chemical Society.",

keywords = "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",

author = "Paulsen, {Eleonora S.} and Jesper Villadsen and Eleonora Tenori and Huizhen Liu and Bonde, {Ditte F.} and Lie, {Mette A.} and Maike Bublitz and Claus Olesen and Autzen, {Henriette E.} and Ingrid Dach and Pankaj Sehgal and Poul Nissen and M{\o}ller, {Jesper V.} and Birgit Schi{\o}tt and Christensen, {S. Br{\o}gger}",

year = "2013",

doi = "10.1021/jm4001083",

language = "English",

volume = "56",

pages = "3609--3619",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "9",

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Paulsen, ES, Villadsen, J, Tenori, E, Liu, H, Bonde, DF, Lie, MA, Bublitz, M, Olesen, C, Autzen, HE, Dach, I, Sehgal, P, Nissen, P, Møller, JV, 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. 3609-3619. https://doi.org/10.1021/jm4001083

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

In: Journal of Medicinal Chemistry, Vol. 56, No. 9, 2013, p. 3609-3619.

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

TY - JOUR

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

AU - Paulsen, Eleonora S.

AU - Villadsen, Jesper

AU - Tenori, Eleonora

AU - Liu, Huizhen

AU - Bonde, Ditte F.

AU - Lie, Mette A.

AU - Bublitz, Maike

AU - Olesen, Claus

AU - Autzen, Henriette E.

AU - Dach, Ingrid

AU - Sehgal, Pankaj

AU - Nissen, Poul

AU - Møller, Jesper V.

AU - Schiøtt, Birgit

AU - Christensen, S. Brøgger

PY - 2013

Y1 - 2013

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. © 2013 American Chemical Society.

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. © 2013 American Chemical Society.

KW - Molecular Medicine

KW - Drug Discovery

KW - sarcoplasmic reticulum calcium transporting adenosine triphosphatase

KW - thapsigargin

KW - water

KW - article

KW - binding affinity

KW - chemical binding

KW - chemical interaction

KW - crystal structure

KW - hydrogen bond

KW - synthesis

KW - Antineoplastic Agents

KW - Hydrogen Bonding

KW - Ligands

KW - Models, Molecular

KW - Protein Binding

KW - Protein Conformation

KW - Sarcoplasmic Reticulum Calcium-Transporting ATPases

KW - Thapsigargin

KW - Water

U2 - 10.1021/jm4001083

DO - 10.1021/jm4001083

M3 - Journal article

C2 - 23574308

VL - 56

SP - 3609

EP - 3619

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 9

ER -

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

Abstract

Keywords

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