Structure, Function and Dynamics in the mur Family of Bacterial Cell Wall Ligases

Smith, Clyde A.

doi:10.1016/j.jmb.2006.07.066

Cited by 156 publications

(161 citation statements)

References 66 publications

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“…While the topologies of the central and C-terminal domains are similar among the Mur ligases, those of the N-terminal domains show differences, with MurC and MurD more closely related to each other than to MurE and MurF. These differences are related to the lengths of the UDP-precursor substrates [10].…”

Section: Introductionmentioning

confidence: 93%

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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Section: Introductionmentioning

confidence: 93%

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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“…The homolog of a bacterial MurE-like ligase (GRMZM2G009070_P01) had highest relative concentration among these pTAC proteins and was 20-fold enriched in nucleoids in comparison with proplastids (Table I). Mur ligases in bacteria are involved in peptidoglycan synthesis for cell walls (Smith, 2006), but homologs in plants are not involved in cell wall biogenesis (Takano and Takechi, 2010). MurE in the moss Physcomitrella patens is localized to the chloroplast, and MurE gene disruption prevented chloroplast division (Machida et al, 2006).…”

Section: Proteins Involved In Transcription and Rna Metabolismmentioning

confidence: 99%

Nucleoid-Enriched Proteomes in Developing Plastids and Chloroplasts from Maize Leaves: A New Conceptual Framework for Nucleoid Functions

et al. 2011

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Plastids contain multiple copies of the plastid chromosome, folded together with proteins and RNA into nucleoids. The degree to which components of the plastid gene expression and protein biogenesis machineries are nucleoid associated, and the factors involved in plastid DNA organization, repair, and replication, are poorly understood. To provide a conceptual framework for nucleoid function, we characterized the proteomes of highly enriched nucleoid fractions of proplastids and mature chloroplasts isolated from the maize (Zea mays) leaf base and tip, respectively, using mass spectrometry. Quantitative comparisons with proteomes of unfractionated proplastids and chloroplasts facilitated the determination of nucleoid-enriched proteins. This nucleoid-enriched proteome included proteins involved in DNA replication, organization, and repair as well as transcription, mRNA processing, splicing, and editing. Many proteins of unknown function, including pentatricopeptide repeat (PPR), tetratricopeptide repeat (TPR), DnaJ, and mitochondrial transcription factor (mTERF) domain proteins, were identified. Strikingly, 70S ribosome and ribosome assembly factors were strongly overrepresented in nucleoid fractions, but protein chaperones were not. Our analysis strongly suggests that mRNA processing, splicing, and editing, as well as ribosome assembly, take place in association with the nucleoid, suggesting that these processes occur cotranscriptionally. The plastid developmental state did not dramatically change the nucleoid-enriched proteome but did quantitatively shift the predominating function from RNA metabolism in undeveloped plastids to translation and homeostasis in chloroplasts. This study extends the known maize plastid proteome by hundreds of proteins, including more than 40 PPR and mTERF domain proteins, and provides a resource for targeted studies on plastid gene expression. Details of protein identification and annotation are provided in the Plant Proteome Database.

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“…An additional MurD N-terminal domain was predicted from 1 to 93 amino acid regions through SCOP analysis. The Nterminal domain responsible for binding the UDP-substrate, the central domain bearing resemblance to the ATP-binding domains of a number of ATP-or GTP-ases, and a Cterminal domain is involved in the binding of the incoming amino acid [36]. Mur ligases have "closed" and "open" conformations, and the closure of the domains is believed to be caused by ligand binding [36].…”

Section: Interrogans Murd As Drug Targetmentioning

confidence: 99%

“…The Nterminal domain responsible for binding the UDP-substrate, the central domain bearing resemblance to the ATP-binding domains of a number of ATP-or GTP-ases, and a Cterminal domain is involved in the binding of the incoming amino acid [36]. Mur ligases have "closed" and "open" conformations, and the closure of the domains is believed to be caused by ligand binding [36]. The MurD of L. interrogans serovars (Copenhageni and Lai) were showing 99% sequence identity and was highly conserved among the leptospires.…”

Section: Interrogans Murd As Drug Targetmentioning

confidence: 99%

Virtual screening for potential inhibitors of homology modeled Leptospira interrogans MurD ligase

2010

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The life-threatening infections caused by Leptospira serovars remain a global challenge since long time. Prevention of infection by controlling environmental factors being difficult to practice in developing countries, there is a need for designing potent anti-leptospirosis drugs. ATP-dependent MurD involved in biosynthesis of peptidoglycan was identified as common drug target among pathogenic Leptospira serovars through subtractive genomic approach. Peptidoglycan biosynthesis pathway being unique to bacteria and absent in host represents promising target for antimicrobial drug discovery. Thus, MurD 3D models were generated using crystal structures of 1EEH and 2JFF as templates in Modeller9v7. Structural refinement and energy minimization of the model was carried out in Maestro 9.0 applying OPLS-AA 2001 force field and was evaluated through Procheck, ProSA, PROQ, and Profile 3D. The active site residues were confirmed from the models in complex with substrate and inhibitor. Four published MurD inhibitors (two phosphinics, one sulfonamide, and one benzene 1,3-dicarbixylic acid derivative) were queried against more than one million entries of Ligand.Info Meta-Database to generate in-house library of 1,496 MurD inhibitor analogs. Our approach of virtual screening of the best-ranked compounds with pharmacokinetics property prediction has provided 17 novel MurD inhibitors for developing anti-leptospirosis drug targeting peptidoglycan biosynthesis pathway.

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Structure, Function and Dynamics in the mur Family of Bacterial Cell Wall Ligases

Cited by 156 publications

References 66 publications

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

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

Nucleoid-Enriched Proteomes in Developing Plastids and Chloroplasts from Maize Leaves: A New Conceptual Framework for Nucleoid Functions

Virtual screening for potential inhibitors of homology modeled Leptospira interrogans MurD ligase

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