Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme.

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 catal...

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Detalles Bibliográficos
Autores: Ferruz Capapey, Noelia, 1988-, Tresadern, Gary, Pineda-Lucena, Antonio, De Fabritiis, Gianni
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/27707
Acceso en línea:http://hdl.handle.net/10230/27707
http://dx.doi.org/10.1038/srep30275
Access Level:acceso abierto
Palabra clave:Molècules
Dinàmica molecular
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spelling Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme.Ferruz Capapey, Noelia, 1988-Tresadern, GaryPineda-Lucena, AntonioDe Fabritiis, GianniMolèculesDinàmica molecularMolecular 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.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.Nature Publishing Group201620162016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/27707http://dx.doi.org/10.1038/srep30275reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésScientific Reports. 2016 Jul 21;6:30275info:eu-repo/grantAgreement/ES/1PE/BIO2014-53095-P© 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/http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/277072026-06-12T07:21:37Z
dc.title.none.fl_str_mv Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme.
title Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme.
spellingShingle Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme.
Ferruz Capapey, Noelia, 1988-
Molècules
Dinàmica molecular
title_short Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme.
title_full Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme.
title_fullStr Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme.
title_full_unstemmed Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme.
title_sort Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme.
dc.creator.none.fl_str_mv Ferruz Capapey, Noelia, 1988-
Tresadern, Gary
Pineda-Lucena, Antonio
De Fabritiis, Gianni
author Ferruz Capapey, Noelia, 1988-
author_facet Ferruz Capapey, Noelia, 1988-
Tresadern, Gary
Pineda-Lucena, Antonio
De Fabritiis, Gianni
author_role author
author2 Tresadern, Gary
Pineda-Lucena, Antonio
De Fabritiis, Gianni
author2_role author
author
author
dc.subject.none.fl_str_mv Molècules
Dinàmica molecular
topic Molècules
Dinàmica molecular
description 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.
publishDate 2016
dc.date.none.fl_str_mv 2016
2016
2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/27707
http://dx.doi.org/10.1038/srep30275
url http://hdl.handle.net/10230/27707
http://dx.doi.org/10.1038/srep30275
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Scientific Reports. 2016 Jul 21;6:30275
info:eu-repo/grantAgreement/ES/1PE/BIO2014-53095-P
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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