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Computational exploration of the binding mode of heme-dependent stimulators into the active catalytic domain of soluble guanylate cyclase.

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dc.contributor Universitat de Vic - Universitat Central de Catalunya. Departament de Biologia de Sistemes
dc.contributor.author Agulló, Luis
dc.contributor.author Gutiérrez de Teran, H.
dc.contributor.author Garcia-Dorado, D.
dc.contributor.author Villà-Freixa, Jordi
dc.contributor.author Buch, Ignasi
dc.date.accessioned 2017-01-12T12:05:29Z
dc.date.available 2017-01-12T12:05:29Z
dc.date.created 2016-10
dc.date.issued 2016-10
dc.identifier.citation Agulló, L., Buch, I., Gutiérrez-de-Terán, H., Garcia-Dorado, D., Villà-Freixa J. (2016). Computational exploration of the binding mode of heme-dependent stimulators into the active catalytic domain of soluble guanylate cyclase. Proteins, 84(10), 1534-1548. doi: 10.1002/prot.25096. es
dc.identifier.issn 1097-0134
dc.identifier.uri http://hdl.handle.net/10854/4798
dc.description.abstract Soluble guanylate cyclase (sGC), the main target of nitric oxide (NO), has been proven to have a significant role in coronary artery disease, pulmonary hypertension, erectile dysfunction, and myocardial infarction. One of its agonists, BAY 41-2272 (Riociguat), has been recently approved for treatment of pulmonary arterial hypertension (PHA), while some others are in clinical phases of development. However, the location of the binding sites for the two known types of agonists, heme-dependent stimulators and heme-independent activators, is a matter of debate, particularly for the first group where both a location on the regulatory (H-NOX) and on the catalytic domain have been suggested by different authors. Here, we address its potential location on the catalytic domain, the unique well characterized at the structural level, by an "in silico" approach. Homology models of the catalytic domain of sGC in "inactive" or "active" conformations were constructed using the structure of previously described crystals of the catalytic domains of "inactive" sGCs (2WZ1, 3ET6) and of "active" adenylate cyclase (1CJU). Each model was submitted to six independent molecular dynamics simulations of about 1 μs. Docking of YC-1, a classic heme-dependent stimulator, to all frames of representative trajectories of "inactive" and "active" conformations, followed by calculation of absolute binding free energies with the linear interaction energy (LIE) method, revealed a potential high-affinity binding site on the "active" structure. The site, located between the pseudo-symmetric and the catalytic site just over the loop β2 -β3 , does not overlap with the forskolin binding site on adenylate cyclases. es
dc.format.extent 15 p. es
dc.language.iso eng es
dc.publisher Wiley Periodicals es
dc.rights Tots els drets reservats es
dc.subject.other Dinàmica molecular es
dc.title Computational exploration of the binding mode of heme-dependent stimulators into the active catalytic domain of soluble guanylate cyclase. es
dc.type info:eu-repo/semantics/article es
dc.identifier.doi https://doi.org/10.1002/prot.25096
dc.rights.accesRights info:eu-repo/semantics/closedAccess es
dc.type.version info:eu-repo/publishedVersion es
dc.indexacio Indexat a WOS/JCR es
dc.indexacio Indexat a SCOPUS es
dc.identifier.data http://dx.doi.org/10.17632/c2fcbs64z6.1

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