Structural insights into the high affinity binding of cardiotonic steroids to the Na+,K+-ATPase

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Structural insights into the high affinity binding of cardiotonic steroids to the Na+,K+-ATPase. / Yatime, Laure; Laursen, Mette; Morth, J Preben; Esmann, Mikael; Nissen, Poul; Fedosova, Natalya U.

I: Journal of Structural Biology, Bind 174, Nr. 2, 2011, s. 296-306.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{6611086691cf4423a854c6a20fc695e7,
title = "Structural insights into the high affinity binding of cardiotonic steroids to the Na+,K+-ATPase",
abstract = "The Na+,K+-ATPase belongs to the P-ATPase family, whose characteristic property is the formation of a phosphorylated intermediate. The enzyme is also a defined target for cardiotonic steroids which inhibit its functional activity and initiate intracellular signaling. Here we describe the 4.6 {\AA} resolution crystal structure of the pig kidney Na+,K+-ATPase in its phosphorylated form stabilized by high affinity binding of the cardiotonic steroid ouabain. The steroid binds to a site formed at transmembrane segments αM1-αM6, plugging the ion pathway from the extracellular side. This structure differs from the previously reported low affinity complex with potassium. Most importantly, the A domain has rotated in response to phosphorylation and αM1-2 move towards the ouabain molecule, providing for high affinity interactions and closing the ion pathway from the extracellular side. The observed re-arrangements of the Na+,K+-ATPase stabilized by cardiotonic steroids may affect protein-protein interactions within the intracellular signal transduction networks.",
keywords = "Animals, Binding Sites, Cardiotonic Agents, Crystallography, X-Ray, Magnesium, Models, Molecular, Ouabain, Phosphorylation, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Sodium-Potassium-Exchanging ATPase, Swine",
author = "Laure Yatime and Mette Laursen and Morth, {J Preben} and Mikael Esmann and Poul Nissen and Fedosova, {Natalya U}",
note = "Copyright {\circledC} 2010 Elsevier Inc. All rights reserved.",
year = "2011",
doi = "10.1016/j.jsb.2010.12.004",
language = "English",
volume = "174",
pages = "296--306",
journal = "Journal of Structural Biology",
issn = "1047-8477",
publisher = "Academic Press",
number = "2",

}

RIS

TY - JOUR

T1 - Structural insights into the high affinity binding of cardiotonic steroids to the Na+,K+-ATPase

AU - Yatime, Laure

AU - Laursen, Mette

AU - Morth, J Preben

AU - Esmann, Mikael

AU - Nissen, Poul

AU - Fedosova, Natalya U

N1 - Copyright © 2010 Elsevier Inc. All rights reserved.

PY - 2011

Y1 - 2011

N2 - The Na+,K+-ATPase belongs to the P-ATPase family, whose characteristic property is the formation of a phosphorylated intermediate. The enzyme is also a defined target for cardiotonic steroids which inhibit its functional activity and initiate intracellular signaling. Here we describe the 4.6 Å resolution crystal structure of the pig kidney Na+,K+-ATPase in its phosphorylated form stabilized by high affinity binding of the cardiotonic steroid ouabain. The steroid binds to a site formed at transmembrane segments αM1-αM6, plugging the ion pathway from the extracellular side. This structure differs from the previously reported low affinity complex with potassium. Most importantly, the A domain has rotated in response to phosphorylation and αM1-2 move towards the ouabain molecule, providing for high affinity interactions and closing the ion pathway from the extracellular side. The observed re-arrangements of the Na+,K+-ATPase stabilized by cardiotonic steroids may affect protein-protein interactions within the intracellular signal transduction networks.

AB - The Na+,K+-ATPase belongs to the P-ATPase family, whose characteristic property is the formation of a phosphorylated intermediate. The enzyme is also a defined target for cardiotonic steroids which inhibit its functional activity and initiate intracellular signaling. Here we describe the 4.6 Å resolution crystal structure of the pig kidney Na+,K+-ATPase in its phosphorylated form stabilized by high affinity binding of the cardiotonic steroid ouabain. The steroid binds to a site formed at transmembrane segments αM1-αM6, plugging the ion pathway from the extracellular side. This structure differs from the previously reported low affinity complex with potassium. Most importantly, the A domain has rotated in response to phosphorylation and αM1-2 move towards the ouabain molecule, providing for high affinity interactions and closing the ion pathway from the extracellular side. The observed re-arrangements of the Na+,K+-ATPase stabilized by cardiotonic steroids may affect protein-protein interactions within the intracellular signal transduction networks.

KW - Animals

KW - Binding Sites

KW - Cardiotonic Agents

KW - Crystallography, X-Ray

KW - Magnesium

KW - Models, Molecular

KW - Ouabain

KW - Phosphorylation

KW - Protein Binding

KW - Protein Structure, Secondary

KW - Protein Structure, Tertiary

KW - Sodium-Potassium-Exchanging ATPase

KW - Swine

U2 - 10.1016/j.jsb.2010.12.004

DO - 10.1016/j.jsb.2010.12.004

M3 - Journal article

C2 - 21182963

VL - 174

SP - 296

EP - 306

JO - Journal of Structural Biology

JF - Journal of Structural Biology

SN - 1047-8477

IS - 2

ER -