Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme.
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- dc.contributor.author Ferruz Capapey, Noelia, 1988-ca
- dc.contributor.author Tresadern, Garyca
- dc.contributor.author Pineda-Lucena, Antonioca
- dc.contributor.author De Fabritiis, Giannica
- dc.date.accessioned 2016-12-07T11:08:32Z
- dc.date.available 2016-12-07T11:08:32Z
- dc.date.issued 2016
- dc.description.abstract Molecular recognition is rarely a two-body protein-ligand problem, as it often involves the dynamic interplay of multiple molecules that together control the binding process. Myo-inositol monophosphatase (IMPase), a drug target for bipolar disorder, depends on 3 Mg(2+) ions as cofactor for its catalytic activity. Although the crystallographic pose of the pre-catalytic complex is well characterized, the binding process by which substrate, cofactor and protein cooperate is essentially unknown. Here, we have characterized cofactor and substrate cooperative binding by means of large-scale molecular dynamics. Our study showed the first and second Mg(2+) ions identify the binding pocket with fast kinetics whereas the third ion presents a much higher energy barrier. Substrate binding can occur in cooperation with cofactor, or alone to a binary or ternary cofactor-IMPase complex, although the last scenario occurs several orders of magnitude faster. Our atomic description of the three-body mechanism offers a particularly challenging example of pathway reconstruction, and may prove particularly useful in realistic contexts where water, ions, cofactors or other entities cooperate and modulate the binding process.ca
- dc.description.sponsorship NF acknowledges support from Generalitat de Catalunya (FI-Agaur). GDF acknowledges support from MINECO (BIO2014-53095-P) and FEDER.We also thank all the volunteers of GPUGRID who donated GPU computing time to the project.
- dc.format.mimetype application/pdfca
- dc.identifier.citation Ferruz N, Tresadern G, Pineda-Lucena A, De Fabritiis G. Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme. Sci Rep. 2016 Jul 21;6:30275. DOI: 10.1038/srep30275ca
- dc.identifier.doi http://dx.doi.org/10.1038/srep30275
- dc.identifier.issn 2045-2322
- dc.identifier.uri http://hdl.handle.net/10230/27707
- dc.language.iso engca
- dc.publisher Nature Publishing Groupca
- dc.relation.ispartof Scientific Reports. 2016 Jul 21;6:30275
- dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BIO2014-53095-P
- dc.rights © 2016, The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ca
- dc.rights.accessRights info:eu-repo/semantics/openAccessca
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/ca
- dc.subject.other Molèculesca
- dc.subject.other Dinàmica molecularca
- dc.title Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme.ca
- dc.type info:eu-repo/semantics/articleca
- dc.type.version info:eu-repo/semantics/publishedVersionca