Targeted molecular dynamics simulation studies of binding and conformational changes in <i>E. coli</i> MurD

Perdih, Andrej; Kotnik, Miha; Hodošček, Milan; Šolmajer, Tom

doi:10.1002/prot.21374

Cited by 53 publications

(47 citation statements)

References 43 publications

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“…In this respect, to assess the influence of the biasing force on the dynamics of the system, we performed a series of TMD simulations using different values for the force constant per atom () and the simulation time (1, 5, and 10 ns). The results discussed in the main paper refer to simulations of 1 ns with , which are consistent with the literature [40], [41], [53]. All TMD simulations performed are detailed in Tab.…”

Section: Methodssupporting

confidence: 84%

“…This was done via targeted molecular dynamics (TMD) simulations [39], which enables to mimic the conformational changes of the protein without explicitly considering the proton transfer and the related energy transduction, which would require the introduction of quantum-mechanical calculations. TMD has been successfully applied to study conformational changes in large systems as [40] and MurD [41], and it has recently been shown to provide reliable transition paths as compared to other methods used to sample conformations of proteins [42]. Note that in this work we are not investigating the issue of substrate specificity of AcrB, which would require additional compounds to be considered.…”

Section: Introductionmentioning

confidence: 99%

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Functional Rotation of the Transporter AcrB: Insights into Drug Extrusion from Simulations

et al. 2010

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The tripartite complex AcrAB-TolC is the major efflux system in Escherichia coli. It extrudes a wide spectrum of noxious compounds out of the bacterium, including many antibiotics. Its active part, the homotrimeric transporter AcrB, is responsible for the selective binding of substrates and energy transduction. Based on available crystal structures and biochemical data, the transport of substrates by AcrB has been proposed to take place via a functional rotation, in which each monomer assumes a particular conformation. However, there is no molecular-level description of the conformational changes associated with the rotation and their connection to drug extrusion. To obtain insights thereon, we have performed extensive targeted molecular dynamics simulations mimicking the functional rotation of AcrB containing doxorubicin, one of the two substrates that were co-crystallized so far. The simulations, including almost half a million atoms, have been used to test several hypotheses concerning the structure-dynamics-function relationship of this transporter. Our results indicate that, upon induction of conformational changes, the substrate detaches from the binding pocket and approaches the gate to the central funnel. Furthermore, we provide strong evidence for the proposed peristaltic transport involving a zipper-like closure of the binding pocket, responsible for the displacement of the drug. A concerted opening of the channel between the binding pocket and the gate further favors the displacement of the drug. This microscopically well-funded information allows one to identify the role of specific amino acids during the transitions and to shed light on the functioning of AcrB.

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Section: Methodssupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Functional Rotation of the Transporter AcrB: Insights into Drug Extrusion from Simulations

et al. 2010

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“…The importance of this carbamoyl group, which is also present in MurE and MurF, has been investigated by chemical rescue experiments (Dementin et al , 2001). Recently, a targeted molecular dynamics study has increased our understanding of the substrate binding and domain closure processes (Perdih et al , 2007).…”

Section: Biosynthesis Of the Udp‐murnac‐peptidesmentioning

confidence: 99%

Cytoplasmic steps of peptidoglycan biosynthesis

et al. 2008

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The biosynthesis of bacterial cell wall peptidoglycan is a complex process that involves enzyme reactions that take place in the cytoplasm (synthesis of the nucleotide precursors) and on the inner side (synthesis of lipid-linked intermediates) and outer side (polymerization reactions) of the cytoplasmic membrane. This review deals with the cytoplasmic steps of peptidoglycan biosynthesis, which can be divided into four sets of reactions that lead to the syntheses of (1) UDP-N-acetylglucosamine from fructose 6-phosphate, (2) UDP-N-acetylmuramic acid from UDP-N-acetylglucosamine, (3) UDP-N-acetylmuramyl-pentapeptide from UDP-N-acetylmuramic acid and (4) D-glutamic acid and dipeptide D-alanyl-D-alanine. Recent data concerning the different enzymes involved are presented. Moreover, special attention is given to (1) the chemical and enzymatic synthesis of the nucleotide precursor substrates that are not commercially available and (2) the search for specific inhibitors that could act as antibacterial compounds.

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“…Furthermore, the open and closed X-ray structures of free and complexed MurD [11e13] and MurF [14,15] show that the Cterminal domain undergoes substantial conformational changes upon substrate or inhibitor binding [16].…”

Section: Introductionmentioning

confidence: 99%

Second-generation sulfonamide inhibitors of d-glutamic acid-adding enzyme: Activity optimisation with conformationally rigid analogues of d-glutamic acid

Sosič¹,

Barreteau²,

Simčič³

et al. 2011

European Journal of Medicinal Chemistry

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a b s t r a c t D-Glutamic acid-adding enzyme (MurD) catalyses the essential addition of D-glutamic acid to the cytoplasmic peptidoglycan precursor UDP-N-acetylmuramoyl-L-alanine, and as such it represents an important antibacterial drug-discovery target enzyme. Based on a series of naphthalene-N-sulfonyl-DGlu derivatives synthesised recently, we synthesised two series of new, optimised sulfonamide inhibitors of MurD that incorporate rigidified mimetics of D-Glu. The compounds that contained either constrained D-Glu or related rigid D-Glu mimetics showed significantly better inhibitory activities than the parent compounds, thereby confirming the advantage of molecular rigidisation in the design of MurD inhibitors. The binding modes of the best inhibitors were examined with high-resolution NMR spectroscopy and X-ray crystallography. We have solved a new crystal structure of the complex of MurD with an inhibitor bearing a 4-aminocyclohexane-1,3-dicarboxyl moiety. These data provide an additional step towards the development of sulfonamide inhibitors with potential antibacterial activities.

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Targeted molecular dynamics simulation studies of binding and conformational changes in E. coli MurD

Cited by 53 publications

References 43 publications

Functional Rotation of the Transporter AcrB: Insights into Drug Extrusion from Simulations

Functional Rotation of the Transporter AcrB: Insights into Drug Extrusion from Simulations

Cytoplasmic steps of peptidoglycan biosynthesis

Second-generation sulfonamide inhibitors of d-glutamic acid-adding enzyme: Activity optimisation with conformationally rigid analogues of d-glutamic acid

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