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Novel stereoselective bufadienolides reveal new insights into the requirements for Na+, K+-ATPase inhibition by cardiotonic steroids

Research output: Contribution to Journal/Magazine › Journal article › peer-review

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Novel stereoselective bufadienolides reveal new insights into the requirements for Na+, K+-ATPase inhibition by cardiotonic steroids. / Tang, Hong-Jin; Ruan, Li-Jun; Tian, Hai-Yan et al.
In: Scientific Reports, Vol. 2016, No. 6, 29155, 05.07.2016.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Tang, H-J, Ruan, L-J, Tian, H-Y, Liang, G-P, Ye, W-C, Hughes, E, Esmann, M, Fedosova, NU, Chung, T-Y, Tzen, JTC, Jiang, R-W & Middleton, DA 2016, 'Novel stereoselective bufadienolides reveal new insights into the requirements for Na+, K+-ATPase inhibition by cardiotonic steroids', Scientific Reports, vol. 2016, no. 6, 29155. https://doi.org/10.1038/srep29155

APA

Tang, H.-J., Ruan, L.-J., Tian, H.-Y., Liang, G.-P., Ye, W.-C., Hughes, E., Esmann, M., Fedosova, N. U., Chung, T.-Y., Tzen, J. T. C., Jiang, R.-W., & Middleton, D. A. (2016). Novel stereoselective bufadienolides reveal new insights into the requirements for Na+, K+-ATPase inhibition by cardiotonic steroids. Scientific Reports, 2016(6), Article 29155. https://doi.org/10.1038/srep29155

Vancouver

Tang HJ, Ruan LJ, Tian HY, Liang GP, Ye WC, Hughes E et al. Novel stereoselective bufadienolides reveal new insights into the requirements for Na+, K+-ATPase inhibition by cardiotonic steroids. Scientific Reports. 2016 Jul 5;2016(6):29155. doi: 10.1038/srep29155

Author

Tang, Hong-Jin ; Ruan, Li-Jun ; Tian, Hai-Yan et al. / Novel stereoselective bufadienolides reveal new insights into the requirements for Na+, K+-ATPase inhibition by cardiotonic steroids. In: Scientific Reports. 2016 ; Vol. 2016, No. 6.

Bibtex

@article{56aef046556e4c60a42fdafb3d6c3a62,
title = "Novel stereoselective bufadienolides reveal new insights into the requirements for Na+, K+-ATPase inhibition by cardiotonic steroids",
abstract = "Cardiotonic steroids (CTS) are clinically important drugs for the treatment of heart failure owing to their potent inhibition of cardiac Na+, K+-ATPase (NKA). Bufadienolides constitute one of the two major classes of CTS, but little is known about how they interact with NKA. We report a remarkable stereoselectivity of NKA inhibition by native 3β-hydroxy bufalin over the 3α-isomer, yet replacing the 3β-hydroxy group with larger polar groups in the same configuration enhances inhibitory potency. Binding of the two 13C-labelled glycosyl diastereomers to NKA were studied by solid-state NMR (SSNMR), which revealed interactions of the glucose group of the 3β- derivative with the inhibitory site, but much weaker interactions of the 3α- derivative with the enzyme. Molecular docking simulations suggest that the polar 3β-groups are closer to the hydrophilic amino acid residues in the entrance of the ligand-binding pocket than those with α-configuration. These first insights into the stereoselective inhibition of NKA by bufadienolides highlight the important role of the hydrophilic moieties at C3 for binding, and may explain why only 3β-hydroxylated bufadienolides are present as a toxic chemical defence in toad venom.",
author = "Hong-Jin Tang and Li-Jun Ruan and Hai-Yan Tian and Guang-Ping Liang and Wen-Cai Ye and Eleri Hughes and Mikael Esmann and Fedosova, {Natalya U.} and Tse-Yu Chung and Tzen, {Jason T. C.} and Ren-Wang Jiang and Middleton, {David Andrew}",
year = "2016",
month = jul,
day = "5",
doi = "10.1038/srep29155",
language = "English",
volume = "2016",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "6",

}

RIS

TY - JOUR

T1 - Novel stereoselective bufadienolides reveal new insights into the requirements for Na+, K+-ATPase inhibition by cardiotonic steroids

AU - Tang, Hong-Jin

AU - Ruan, Li-Jun

AU - Tian, Hai-Yan

AU - Liang, Guang-Ping

AU - Ye, Wen-Cai

AU - Hughes, Eleri

AU - Esmann, Mikael

AU - Fedosova, Natalya U.

AU - Chung, Tse-Yu

AU - Tzen, Jason T. C.

AU - Jiang, Ren-Wang

AU - Middleton, David Andrew

PY - 2016/7/5

Y1 - 2016/7/5

N2 - Cardiotonic steroids (CTS) are clinically important drugs for the treatment of heart failure owing to their potent inhibition of cardiac Na+, K+-ATPase (NKA). Bufadienolides constitute one of the two major classes of CTS, but little is known about how they interact with NKA. We report a remarkable stereoselectivity of NKA inhibition by native 3β-hydroxy bufalin over the 3α-isomer, yet replacing the 3β-hydroxy group with larger polar groups in the same configuration enhances inhibitory potency. Binding of the two 13C-labelled glycosyl diastereomers to NKA were studied by solid-state NMR (SSNMR), which revealed interactions of the glucose group of the 3β- derivative with the inhibitory site, but much weaker interactions of the 3α- derivative with the enzyme. Molecular docking simulations suggest that the polar 3β-groups are closer to the hydrophilic amino acid residues in the entrance of the ligand-binding pocket than those with α-configuration. These first insights into the stereoselective inhibition of NKA by bufadienolides highlight the important role of the hydrophilic moieties at C3 for binding, and may explain why only 3β-hydroxylated bufadienolides are present as a toxic chemical defence in toad venom.

AB - Cardiotonic steroids (CTS) are clinically important drugs for the treatment of heart failure owing to their potent inhibition of cardiac Na+, K+-ATPase (NKA). Bufadienolides constitute one of the two major classes of CTS, but little is known about how they interact with NKA. We report a remarkable stereoselectivity of NKA inhibition by native 3β-hydroxy bufalin over the 3α-isomer, yet replacing the 3β-hydroxy group with larger polar groups in the same configuration enhances inhibitory potency. Binding of the two 13C-labelled glycosyl diastereomers to NKA were studied by solid-state NMR (SSNMR), which revealed interactions of the glucose group of the 3β- derivative with the inhibitory site, but much weaker interactions of the 3α- derivative with the enzyme. Molecular docking simulations suggest that the polar 3β-groups are closer to the hydrophilic amino acid residues in the entrance of the ligand-binding pocket than those with α-configuration. These first insights into the stereoselective inhibition of NKA by bufadienolides highlight the important role of the hydrophilic moieties at C3 for binding, and may explain why only 3β-hydroxylated bufadienolides are present as a toxic chemical defence in toad venom.

U2 - 10.1038/srep29155

DO - 10.1038/srep29155

M3 - Journal article

VL - 2016

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 6

M1 - 29155

ER -