Epoxide Hydrolase Conformational Heterogeneity for the Resolution of Bulky Pharmacologically Relevant Epoxide Substrates
dc.contributor.author
dc.date.accessioned
2019-03-25T11:31:09Z
dc.date.available
2019-03-25T11:31:09Z
dc.date.issued
2018-08-22
dc.identifier.issn
0947-6539
dc.identifier.uri
dc.description.abstract
The conformational landscape of Bacillus megaterium epoxide hydrolase (BmEH) and how it is altered by mutations that confer the enzyme the ability to accept bulky epoxide substrates has been investigated. Extensive molecular dynamics (MD) simulations coupled to active site volume calculations have unveiled relevant features of the enzyme conformational dynamics and function. Our long-timescale MD simulations identify key conformational states not previously observed by means of X-ray crystallography and short MD simulations that present the loop containing one of the catalytic residues, Asp239, in a wide-open conformation, which is likely involved in the binding of the epoxide substrate. Introduction of mutations M145S and F128A dramatically alters the conformational landscape of the enzyme. These singly mutated variants can accept bulky epoxide substrates due to the disorder induced by mutation in the α-helix containing the catalytic Tyr144 and some parts of the lid domain. These changes impact the enzyme active site, which is substantially wider and more complementary to the bulky pharmacologically relevant epoxide substrates
dc.description.sponsorship
E. S.-H. thanks the Generalitat de Catalunya for a PhD fellowship (2017-FI-B-00118), M. G.-B is grateful to the Ramón Areces Foundation for a Postdoctoral Fellowship. F.F. thanks the European Community for MSCA-IF-2014-EF-661160-MetAccembly grant. S. O. thanks the Spanish MINECO CTQ2014-59212-P, Ramón y Cajal contract (RYC-2014-16846), the European Community for CIG project (PCIG14-GA-2013-630978), and the funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-2015-StG-679001). We thank the Generalitat de Catalunya for grup emergent 2017 SGR-1707
dc.format.mimetype
application/pdf
dc.language.iso
eng
dc.publisher
Wiley
dc.relation
info:eu-repo/grantAgreement/MINECO//CTQ2014-59212-P/ES/SPIN STATE AND ENZYMATIC CATALYSIS BASED ON BOTTOM-UP COMPUTATIONAL DESIGN/
dc.relation.isformatof
Versió postprint del document publicat a: https://doi.org/10.1002/chem.201801068
dc.relation.ispartof
© Chemistry - A European Journal, 2018, vol. 24, núm. 47, p. 12254-12258
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Articles publicats (D-Q)
Articles publicats (D-Q)
dc.rights
Tots els drets reservats
dc.subject
dc.title
Epoxide Hydrolase Conformational Heterogeneity for the Resolution of Bulky Pharmacologically Relevant Epoxide Substrates
dc.type
info:eu-repo/semantics/article
dc.rights.accessRights
info:eu-repo/semantics/openAccess
dc.date.embargoEndDate
info:eu-repo/date/embargoEnd/2019-08-22
dc.relation.projectID
info:eu-repo/grantAgreement/EC/FP7/630978/EU/Computational Exploration of Directed Evolution rules for tuning enzymatic activities/DIREVENZYME
info:eu-repo/grantAgreement/EC/H2020/679001/EU/Network models for the computational design of proficient enzymes/NetMoDEzyme
dc.type.version
info:eu-repo/semantics/acceptedVersion
dc.identifier.doi
dc.identifier.idgrec
028553
dc.contributor.funder
dc.type.peerreviewed
peer-reviewed
dc.relation.ProjectAcronym
dc.identifier.eissn
1521-3765