Identification of the molecular site of ivabradine binding to HCN4 channels.

Ivabradine is a specific heart rate-reducing agent approved as a treatment of chronic stable angina. Its mode of action involves a selective and specific block of HCN channels, the molecular components of sinoatrial "funny" (f)-channels. Different studies suggest that the binding site of i...

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Autores principales:	Annalisa Bucchi, Mirko Baruscotti, Marco Nardini, Andrea Barbuti, Stefano Micheloni, Martino Bolognesi, Dario DiFrancesco
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6779caee5bf1410c9d6a58ff18238140
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spelling	oai:doaj.org-article:6779caee5bf1410c9d6a58ff182381402021-11-18T08:02:40ZIdentification of the molecular site of ivabradine binding to HCN4 channels.1932-620310.1371/journal.pone.0053132https://doaj.org/article/6779caee5bf1410c9d6a58ff182381402013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23308150/?tool=EBIhttps://doaj.org/toc/1932-6203Ivabradine is a specific heart rate-reducing agent approved as a treatment of chronic stable angina. Its mode of action involves a selective and specific block of HCN channels, the molecular components of sinoatrial "funny" (f)-channels. Different studies suggest that the binding site of ivabradine is located in the inner vestibule of HCN channels, but the molecular details of ivabradine binding are unknown. We thus sought to investigate by mutagenesis and in silico analysis which residues of the HCN4 channel, the HCN isoform expressed in the sinoatrial node, are involved in the binding of ivabradine. Using homology modeling, we verified the presence of an inner cavity below the channel pore and identified residues lining the cavity; these residues were replaced with alanine (or valine) either alone or in combination, and WT and mutant channels were expressed in HEK293 cells. Comparison of the block efficiency of mutant vs WT channels, measured by patch-clamp, revealed that residues Y506, F509 and I510 are involved in ivabradine binding. For each mutant channel, docking simulations correctly explain the reduced block efficiency in terms of proportionally reduced affinity for ivabradine binding. In summary our study shows that ivabradine occupies a cavity below the channel pore, and identifies specific residues facing this cavity that interact and stabilize the ivabradine molecule. This study provides an interpretation of known properties of f/HCN4 channel block by ivabradine such as the "open channel block", the current-dependence of block and the property of "trapping" of drug molecules in the closed configuration.Annalisa BucchiMirko BaruscottiMarco NardiniAndrea BarbutiStefano MicheloniMartino BolognesiDario DiFrancescoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 1, p e53132 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Annalisa Bucchi Mirko Baruscotti Marco Nardini Andrea Barbuti Stefano Micheloni Martino Bolognesi Dario DiFrancesco Identification of the molecular site of ivabradine binding to HCN4 channels.
description	Ivabradine is a specific heart rate-reducing agent approved as a treatment of chronic stable angina. Its mode of action involves a selective and specific block of HCN channels, the molecular components of sinoatrial "funny" (f)-channels. Different studies suggest that the binding site of ivabradine is located in the inner vestibule of HCN channels, but the molecular details of ivabradine binding are unknown. We thus sought to investigate by mutagenesis and in silico analysis which residues of the HCN4 channel, the HCN isoform expressed in the sinoatrial node, are involved in the binding of ivabradine. Using homology modeling, we verified the presence of an inner cavity below the channel pore and identified residues lining the cavity; these residues were replaced with alanine (or valine) either alone or in combination, and WT and mutant channels were expressed in HEK293 cells. Comparison of the block efficiency of mutant vs WT channels, measured by patch-clamp, revealed that residues Y506, F509 and I510 are involved in ivabradine binding. For each mutant channel, docking simulations correctly explain the reduced block efficiency in terms of proportionally reduced affinity for ivabradine binding. In summary our study shows that ivabradine occupies a cavity below the channel pore, and identifies specific residues facing this cavity that interact and stabilize the ivabradine molecule. This study provides an interpretation of known properties of f/HCN4 channel block by ivabradine such as the "open channel block", the current-dependence of block and the property of "trapping" of drug molecules in the closed configuration.
format	article
author	Annalisa Bucchi Mirko Baruscotti Marco Nardini Andrea Barbuti Stefano Micheloni Martino Bolognesi Dario DiFrancesco
author_facet	Annalisa Bucchi Mirko Baruscotti Marco Nardini Andrea Barbuti Stefano Micheloni Martino Bolognesi Dario DiFrancesco
author_sort	Annalisa Bucchi
title	Identification of the molecular site of ivabradine binding to HCN4 channels.
title_short	Identification of the molecular site of ivabradine binding to HCN4 channels.
title_full	Identification of the molecular site of ivabradine binding to HCN4 channels.
title_fullStr	Identification of the molecular site of ivabradine binding to HCN4 channels.
title_full_unstemmed	Identification of the molecular site of ivabradine binding to HCN4 channels.
title_sort	identification of the molecular site of ivabradine binding to hcn4 channels.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/6779caee5bf1410c9d6a58ff18238140
work_keys_str_mv	AT annalisabucchi identificationofthemolecularsiteofivabradinebindingtohcn4channels AT mirkobaruscotti identificationofthemolecularsiteofivabradinebindingtohcn4channels AT marconardini identificationofthemolecularsiteofivabradinebindingtohcn4channels AT andreabarbuti identificationofthemolecularsiteofivabradinebindingtohcn4channels AT stefanomicheloni identificationofthemolecularsiteofivabradinebindingtohcn4channels AT martinobolognesi identificationofthemolecularsiteofivabradinebindingtohcn4channels AT dariodifrancesco identificationofthemolecularsiteofivabradinebindingtohcn4channels
_version_	1718422607413379072

Identification of the molecular site of ivabradine binding to HCN4 channels.

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