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dc.contributor.authorGordon, SE
dc.contributor.authorWeber, DK
dc.contributor.authorDownton, MT
dc.contributor.authorWagner, J
dc.contributor.authorPerugini, MA
dc.date.accessioned2020-12-22T06:04:09Z
dc.date.available2020-12-22T06:04:09Z
dc.date.issued2016-03-01
dc.identifierpii: PCOMPBIOL-D-15-01473
dc.identifier.citationGordon, S. E., Weber, D. K., Downton, M. T., Wagner, J. & Perugini, M. A. (2016). Dynamic Modelling Reveals 'Hotspots' on the Pathway to Enzyme-Substrate Complex Formation. PLOS COMPUTATIONAL BIOLOGY, 12 (3), https://doi.org/10.1371/journal.pcbi.1004811.
dc.identifier.issn1553-734X
dc.identifier.urihttp://hdl.handle.net/11343/258411
dc.description.abstractDihydrodipicolinate synthase (DHDPS) catalyzes the first committed step in the diaminopimelate pathway of bacteria, yielding amino acids required for cell wall and protein biosyntheses. The essentiality of the enzyme to bacteria, coupled with its absence in humans, validates DHDPS as an antibacterial drug target. Conventional drug design efforts have thus far been unsuccessful in identifying potent DHDPS inhibitors. Here, we make use of contemporary molecular dynamics simulation and Markov state models to explore the interactions between DHDPS from the human pathogen Staphylococcus aureus and its cognate substrate, pyruvate. Our simulations recover the crystallographic DHDPS-pyruvate complex without a priori knowledge of the final bound structure. The highly conserved residue Arg140 was found to have a pivotal role in coordinating the entry of pyruvate into the active site from bulk solvent, consistent with previous kinetic reports, indicating an indirect role for the residue in DHDPS catalysis. A metastable binding intermediate characterized by multiple points of intermolecular interaction between pyruvate and key DHDPS residue Arg140 was found to be a highly conserved feature of the binding trajectory when comparing alternative binding pathways. By means of umbrella sampling we show that these binding intermediates are thermodynamically metastable, consistent with both the available experimental data and the substrate binding model presented in this study. Our results provide insight into an important enzyme-substrate interaction in atomistic detail that offers the potential to be exploited for the discovery of more effective DHDPS inhibitors and, in a broader sense, dynamic protein-drug interactions.
dc.languageEnglish
dc.publisherPUBLIC LIBRARY SCIENCE
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleDynamic Modelling Reveals 'Hotspots' on the Pathway to Enzyme-Substrate Complex Formation
dc.typeJournal Article
dc.identifier.doi10.1371/journal.pcbi.1004811
melbourne.affiliation.departmentBiochemistry and Molecular Biology
melbourne.source.titlePLoS Computational Biology
melbourne.source.volume12
melbourne.source.issue3
dc.rights.licenseCC BY
melbourne.elementsid1041919
melbourne.contributor.authorPerugini, Matthew
dc.identifier.eissn1553-7358
melbourne.accessrightsOpen Access


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