Binding of cardiotonic steroids to Na+,K+-ATPase in the E2P state

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Standard

Binding of cardiotonic steroids to Na+,K+-ATPase in the E2P state. / Kanai, Ryuta; Cornelius, Flemming; Ogawa, Haruo et al.

I: Proceedings of the National Academy of Sciences of the United States of America, Bind 118, Nr. 1, e2020438118, 01.2021.

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

Harvard

Kanai, R, Cornelius, F, Ogawa, H, Motoyama, K, Vilsen, B & Toyoshima, C 2021, 'Binding of cardiotonic steroids to Na+,K+-ATPase in the E2P state', Proceedings of the National Academy of Sciences of the United States of America, bind 118, nr. 1, e2020438118. https://doi.org/10.1073/pnas.2020438118

APA

Kanai, R., Cornelius, F., Ogawa, H., Motoyama, K., Vilsen, B., & Toyoshima, C. (2021). Binding of cardiotonic steroids to Na+,K+-ATPase in the E2P state. Proceedings of the National Academy of Sciences of the United States of America, 118(1), [e2020438118]. https://doi.org/10.1073/pnas.2020438118

CBE

Kanai R, Cornelius F, Ogawa H, Motoyama K, Vilsen B, Toyoshima C. 2021. Binding of cardiotonic steroids to Na+,K+-ATPase in the E2P state. Proceedings of the National Academy of Sciences of the United States of America. 118(1):Article e2020438118. https://doi.org/10.1073/pnas.2020438118

MLA

Kanai, Ryuta et al. "Binding of cardiotonic steroids to Na+,K+-ATPase in the E2P state". Proceedings of the National Academy of Sciences of the United States of America. 2021. 118(1). https://doi.org/10.1073/pnas.2020438118

Vancouver

Kanai R, Cornelius F, Ogawa H, Motoyama K, Vilsen B, Toyoshima C. Binding of cardiotonic steroids to Na+,K+-ATPase in the E2P state. Proceedings of the National Academy of Sciences of the United States of America. 2021 jan.;118(1). e2020438118. https://doi.org/10.1073/pnas.2020438118

Author

Kanai, Ryuta ; Cornelius, Flemming ; Ogawa, Haruo et al. / Binding of cardiotonic steroids to Na+,K+-ATPase in the E2P state. I: Proceedings of the National Academy of Sciences of the United States of America. 2021 ; Bind 118, Nr. 1.

Bibtex

@article{ff553743eb034e7faa1193f824ce5dc1,
title = "Binding of cardiotonic steroids to Na+,K+-ATPase in the E2P state",
abstract = "The sodium pump (Na+, K+-ATPase, NKA) is vital for animal cells, as it actively maintains Na+ and K+ electrochemical gradients across the cell membrane. It is a target of cardiotonic steroids (CTSs) such as ouabain and digoxin. As CTSs are almost unique strong inhibitors specific to NKA, a wide range of derivatives has been developed for potential therapeutic use. Several crystal structures have been published for NKA-CTS complexes, but they fail to explain the largely different inhibitory properties of the various CTSs. For instance, although CTSs are thought to inhibit ATPase activity by binding to NKA in the E2P state, we do not know if large conformational changes accompany binding, as no crystal structure is available for the E2P state free of CTS. Here, we describe crystal structures of the BeF3- complex of NKA representing the E2P ground state and then eight crystal structures of seven CTSs, including rostafuroxin and istaroxime, two new members under clinical trials, in complex with NKA in the E2P state. The conformations of NKA are virtually identical in all complexes with and without CTSs, showing that CTSs bind to a preformed cavity in NKA. By comparing the inhibitory potency of the CTSs measured under four different conditions, we elucidate how different structural features of the CTSs result in different inhibitory properties. The crystal structures also explain K+(+)-antagonism and suggest a route to isoform specific CTSs.",
keywords = "cardiotonic steroids, Na+,K+-ATPase, crystal structures, isoform specificity, sodium pump, SITE-DIRECTED MUTAGENESIS, NA,K-ATPASE ALPHA-SUBUNIT, SODIUM-POTASSIUM PUMP, CRYSTAL-STRUCTURE, K+-ATPASE, INORGANIC-PHOSPHATE, LIGAND-BINDING, P-I, OUABAIN, NA+",
author = "Ryuta Kanai and Flemming Cornelius and Haruo Ogawa and Kanna Motoyama and Bente Vilsen and Chikashi Toyoshima",
year = "2021",
month = jan,
doi = "10.1073/pnas.2020438118",
language = "English",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "1",

}

RIS

TY - JOUR

T1 - Binding of cardiotonic steroids to Na+,K+-ATPase in the E2P state

AU - Kanai, Ryuta

AU - Cornelius, Flemming

AU - Ogawa, Haruo

AU - Motoyama, Kanna

AU - Vilsen, Bente

AU - Toyoshima, Chikashi

PY - 2021/1

Y1 - 2021/1

N2 - The sodium pump (Na+, K+-ATPase, NKA) is vital for animal cells, as it actively maintains Na+ and K+ electrochemical gradients across the cell membrane. It is a target of cardiotonic steroids (CTSs) such as ouabain and digoxin. As CTSs are almost unique strong inhibitors specific to NKA, a wide range of derivatives has been developed for potential therapeutic use. Several crystal structures have been published for NKA-CTS complexes, but they fail to explain the largely different inhibitory properties of the various CTSs. For instance, although CTSs are thought to inhibit ATPase activity by binding to NKA in the E2P state, we do not know if large conformational changes accompany binding, as no crystal structure is available for the E2P state free of CTS. Here, we describe crystal structures of the BeF3- complex of NKA representing the E2P ground state and then eight crystal structures of seven CTSs, including rostafuroxin and istaroxime, two new members under clinical trials, in complex with NKA in the E2P state. The conformations of NKA are virtually identical in all complexes with and without CTSs, showing that CTSs bind to a preformed cavity in NKA. By comparing the inhibitory potency of the CTSs measured under four different conditions, we elucidate how different structural features of the CTSs result in different inhibitory properties. The crystal structures also explain K+(+)-antagonism and suggest a route to isoform specific CTSs.

AB - The sodium pump (Na+, K+-ATPase, NKA) is vital for animal cells, as it actively maintains Na+ and K+ electrochemical gradients across the cell membrane. It is a target of cardiotonic steroids (CTSs) such as ouabain and digoxin. As CTSs are almost unique strong inhibitors specific to NKA, a wide range of derivatives has been developed for potential therapeutic use. Several crystal structures have been published for NKA-CTS complexes, but they fail to explain the largely different inhibitory properties of the various CTSs. For instance, although CTSs are thought to inhibit ATPase activity by binding to NKA in the E2P state, we do not know if large conformational changes accompany binding, as no crystal structure is available for the E2P state free of CTS. Here, we describe crystal structures of the BeF3- complex of NKA representing the E2P ground state and then eight crystal structures of seven CTSs, including rostafuroxin and istaroxime, two new members under clinical trials, in complex with NKA in the E2P state. The conformations of NKA are virtually identical in all complexes with and without CTSs, showing that CTSs bind to a preformed cavity in NKA. By comparing the inhibitory potency of the CTSs measured under four different conditions, we elucidate how different structural features of the CTSs result in different inhibitory properties. The crystal structures also explain K+(+)-antagonism and suggest a route to isoform specific CTSs.

KW - cardiotonic steroids

KW - Na+,K+-ATPase

KW - crystal structures

KW - isoform specificity

KW - sodium pump

KW - SITE-DIRECTED MUTAGENESIS

KW - NA,K-ATPASE ALPHA-SUBUNIT

KW - SODIUM-POTASSIUM PUMP

KW - CRYSTAL-STRUCTURE

KW - K+-ATPASE

KW - INORGANIC-PHOSPHATE

KW - LIGAND-BINDING

KW - P-I

KW - OUABAIN

KW - NA+

U2 - 10.1073/pnas.2020438118

DO - 10.1073/pnas.2020438118

M3 - Journal article

C2 - 33318128

VL - 118

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 1

M1 - e2020438118

ER -