dc.contributor.authorChen, Ming Wei
dc.contributor.authorLohkamp, Bernhard
dc.contributor.authorSchnell, Robert
dc.contributor.authorLescar, Julien
dc.contributor.authorSchneider, Gunter
dc.date.accessioned2013-07-22T02:43:07Z
dc.date.available2013-07-22T02:43:07Z
dc.date.copyright2013en_US
dc.date.issued2013
dc.identifier.citationChen, M. W., Lohkamp, B., Schnell, R., Lescar, J., & Schneider, G. (2013). Substrate Channel Flexibility in Pseudomonas aeruginosa MurB Accommodates Two Distinct Substrates. PLoS ONE, 8(6), e66936.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://hdl.handle.net/10220/11918
dc.description.abstractBiosynthesis of UDP-N-acetylmuramic acid in bacteria is a committed step towards peptidoglycan production. In an NADPH- and FAD-dependent reaction, the UDP-N-acetylglucosamine-enolpyruvate reductase (MurB) reduces UDP-N-acetylglucosamine-enolpyruvate to UDP-N-acetylmuramic acid. We determined the three-dimensional structures of the ternary complex of Pseudomonas aeruginosa MurB with FAD and NADP+ in two crystal forms to resolutions of 2.2 and 2.1 Å, respectively, to investigate the structural basis of the first half-reaction, hydride transfer from NADPH to FAD. The nicotinamide ring of NADP+ stacks against the si face of the isoalloxazine ring of FAD, suggesting an unusual mode of hydride transfer to flavin. Comparison with the structure of the Escherichia coli MurB complex with UDP-N-acetylglucosamine-enolpyruvate shows that both substrates share the binding site located between two lobes of the substrate-binding domain III, consistent with a ping pong mechanism with sequential substrate binding. The nicotinamide and the enolpyruvyl moieties are strikingly well-aligned upon superimposition, both positioned for hydride transfer to and from FAD. However, flexibility of the substrate channel allows the non-reactive parts of the two substrates to bind in different conformations. A potassium ion in the active site may assist in substrate orientation and binding. These structural models should help in structure-aided drug design against MurB, which is essential for cell wall biogenesis and hence bacterial survival.en_US
dc.language.isoenen_US
dc.relation.ispartofseriesPLoS ONEen_US
dc.rights© 2013 The Authors. This paper was published in PLoS ONE and is made available as an electronic reprint (preprint) with permission of The Authors. The paper can be found at the following official DOI: [http://dx.doi.org/10.1371/journal.pone.0066936]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law.en_US
dc.subjectDRNTU::Science::Biological sciences
dc.titleSubstrate channel flexibility in Pseudomonas aeruginosa MurB accommodates two distinct substratesen_US
dc.typeJournal Article
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0066936
dc.description.versionPublished versionen_US


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