Structural analysis of the contacts anchoring moenomycin to peptidoglycan glycosyltransferases and implications for antibiotic design.

Abstract:

:Peptidoglycan glycosyltransferases (PGTs), enzymes that catalyze the formation of the glycan chains of the bacterial cell wall, have tremendous potential as antibiotic targets. The moenomycins, a potent family of natural product antibiotics, are the only known active site inhibitors of the PGTs and serve as blueprints for the structure-based design of new antibacterials. A 2.8 A structure of a Staphylococcus aureus PGT with moenomycin A bound in the active site appeared recently, potentially providing insight into substrate binding; however, the protein-ligand contacts were not analyzed in detail and the implications of the structure for inhibitor design were not addressed. We report here the 2.3 A structure of a complex of neryl-moenomycin A bound to the PGT domain of Aquifex aeolicus PBP1A. The structure allows us to examine protein-ligand contacts in detail and implies that six conserved active site residues contact the centrally located F-ring phosphoglycerate portion of neryl-moenomycin A. A mutational analysis shows that all six residues play important roles in enzymatic activity. We suggest that small scaffolds that maintain these key contacts will serve as effective PGT inhibitors. To test this hypothesis, we have prepared, via heterologous expression of a subset of moenomycin biosynthetic genes, a novel moenomycin intermediate that maintains these six contacts but does not contain the putative minimal pharmacophore. This compound has comparable biological activity to the previously proposed minimal pharmacophore. The results reported here may facilitate the design of antibiotics targeted against peptidoglycan glycosyltransferases.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Yuan Y,Fuse S,Ostash B,Sliz P,Kahne D,Walker S

doi

10.1021/cb800078a

subject

Has Abstract

pub_date

2008-07-18 00:00:00

pages

429-36

issue

7

eissn

1554-8929

issn

1554-8937

journal_volume

3

pub_type

杂志文章
  • Role of stoichiometry in the dimer-stabilizing effect of AMPA receptor allosteric modulators.

    abstract::Protein dimerization provides a mechanism for the modulation of cellular signaling events. In α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors, the rapidly desensitizing, activated state has been correlated with a weakly dimeric, glutamate-binding domain conformation. Allosteric modulators can fo...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb4007166

    authors: Ptak CP,Hsieh CL,Weiland GA,Oswald RE

    更新日期:2014-01-17 00:00:00

  • A synthetic derivative of plant allylpolyalkoxybenzenes induces selective loss of motile cilia in sea urchin embryos.

    abstract::Polyalkoxybenzenes are plant components displaying a wide range of biological activities. In these studies, we synthesized apiol and dillapiol isoxazoline analogues of combretastatins and evaluated their effect on sea urchin embryos. We have shown that p-methoxyphenyl isoxazoline caused sea urchin embryo immobilizatio...

    journal_title:ACS chemical biology

    pub_type: 信件

    doi:10.1021/cb700163q

    authors: Semenova MN,Tsyganov DV,Yakubov AP,Kiselyov AS,Semenov VV

    更新日期:2008-02-15 00:00:00

  • DprE1 Is a Vulnerable Tuberculosis Drug Target Due to Its Cell Wall Localization.

    abstract::The flavo-enzyme DprE1 catalyzes a key epimerization step in the decaprenyl-phosphoryl d-arabinose (DPA) pathway, which is essential for mycobacterial cell wall biogenesis and targeted by several new tuberculosis drug candidates. Here, using differential radiolabeling with DPA precursors and high-resolution fluorescen...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.5b00237

    authors: Brecik M,Centárová I,Mukherjee R,Kolly GS,Huszár S,Bobovská A,Kilacsková E,Mokošová V,Svetlíková Z,Šarkan M,Neres J,Korduláková J,Cole ST,Mikušová K

    更新日期:2015-07-17 00:00:00

  • Structural Chemistry of Human RNA Methyltransferases.

    abstract::RNA methyltransferases (RNMTs) play important roles in RNA stability, splicing, and epigenetic mechanisms. They constitute a promising target class that is underexplored by the medicinal chemistry community. Information of relevance to drug design can be extracted from the rich structural coverage of human RNMTs. In t...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.5b00781

    authors: Schapira M

    更新日期:2016-03-18 00:00:00

  • Use of calculated cation-pi binding energies to predict relative strengths of nicotinic acetylcholine receptor agonists.

    abstract::Agonists and antagonists of the nicotinic acetylcholine receptor (nAChR) are used to treat nicotine addiction, neuromuscular disorders, and neurological diseases. In designing small molecule therapeutics with the nAChR as a target, it is useful to identify chemical parameters that correlate with ability to activate th...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb800189y

    authors: Tantama M,Licht S

    更新日期:2008-11-21 00:00:00

  • Ligand Discovery for a Peptide-Binding GPCR by Structure-Based Screening of Fragment- and Lead-Like Chemical Libraries.

    abstract::Peptide-recognizing G protein-coupled receptors (GPCRs) are promising therapeutic targets but often resist drug discovery efforts. Determination of crystal structures for peptide-binding GPCRs has provided opportunities to explore structure-based methods in lead development. Molecular docking screens of two chemical l...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.6b00646

    authors: Ranganathan A,Heine P,Rudling A,Plückthun A,Kummer L,Carlsson J

    更新日期:2017-03-17 00:00:00

  • Small molecule inhibitors of bromodomain-acetyl-lysine interactions.

    abstract::Bromodomains are protein modules that bind to acetylated lysine residues. Their interaction with histone proteins suggests that they function as "readers" of histone lysine acetylation, a component of the proposed "histone code". Bromodomain-containing proteins are often found as components of larger protein complexes...

    journal_title:ACS chemical biology

    pub_type: 杂志文章,评审

    doi:10.1021/cb500996u

    authors: Brand M,Measures AR,Wilson BG,Cortopassi WA,Alexander R,Höss M,Hewings DS,Rooney TP,Paton RS,Conway SJ

    更新日期:2015-01-16 00:00:00

  • Biocatalytic Detoxification of Paralytic Shellfish Toxins.

    abstract::Small molecules that bind to voltage-gated sodium channels (VGSCs) are promising leads in the treatment of numerous neurodegenerative diseases and pain. Nature is a highly skilled medicinal chemist in this regard, designing potent VGSC ligands capable of binding to and blocking the channel, thereby offering compounds ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.9b00123

    authors: Lukowski AL,Denomme N,Hinze ME,Hall S,Isom LL,Narayan ARH

    更新日期:2019-05-17 00:00:00

  • Lysine-specific histone demethylase 1 inhibitors control breast cancer proliferation in ERα-dependent and -independent manners.

    abstract::Lysine specific demethylase 1 (LSD1, also known as KDM1) is a histone modifying enzyme that regulates the expression of many genes important in cancer progression and proliferation. It is present in various transcriptional complexes including those containing the estrogen receptor (ER). Indeed, inhibition of LSD1 acti...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb300108c

    authors: Pollock JA,Larrea MD,Jasper JS,McDonnell DP,McCafferty DG

    更新日期:2012-07-20 00:00:00

  • Small molecule signaling in Caenorhabditis elegans.

    abstract::Whereas the C. elegans genome was sequenced many years ago, the role of small molecule signals in its biology is still poorly understood. A recent publication reports the identification of two steroidal signaling molecules that regulate C. elegans reproductive development and dauer diapause via the nuclear receptor DA...

    journal_title:ACS chemical biology

    pub_type: 杂志文章,评审

    doi:10.1021/cb600173t

    authors: Schroeder FC

    更新日期:2006-05-23 00:00:00

  • Parietal Structures of Escherichia coli Can Impact the D-Cateslytin Antibacterial Activity.

    abstract::Bacterial resistance to conventional antibiotics is of major concern. Antimicrobial peptides (AMPs) are considered excellent alternatives. Among them, D-cateslytin (D-Ctl, derivative of a host defense peptide) has shown high efficiency against a broad spectrum of bacteria. The first target of AMPs is the outer membran...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.0c00622

    authors: Quilès F,Barth D,Peric O,Fantner GE,Francius G

    更新日期:2020-10-16 00:00:00

  • Cruentaren A binds F1F0 ATP synthase to modulate the Hsp90 protein folding machinery.

    abstract::The molecular chaperone Hsp90 requires the assistance of immunophilins, co-chaperones, and partner proteins for the conformational maturation of client proteins. Hsp90 inhibition represents a promising anticancer strategy due to the dependence of numerous oncogenic signaling pathways upon Hsp90 function. Historically,...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb400906e

    authors: Hall JA,Kusuma BR,Brandt GE,Blagg BS

    更新日期:2014-04-18 00:00:00

  • Characterization of CYP115 As a Gibberellin 3-Oxidase Indicates That Certain Rhizobia Can Produce Bioactive Gibberellin A4.

    abstract::The gibberellin (GA) phytohormones are produced not only by plants but also by fungi and bacteria. Previous characterization of a cytochrome P450 (CYP)-rich GA biosynthetic operon found in many symbiotic, nitrogen-fixing rhizobia led to the elucidation of bacterial GA biosynthesis and implicated GA9 as the final produ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.6b01038

    authors: Nett RS,Contreras T,Peters RJ

    更新日期:2017-04-21 00:00:00

  • Features of modularly assembled compounds that impart bioactivity against an RNA target.

    abstract::Transcriptomes provide a myriad of potential RNAs that could be the targets of therapeutics or chemical genetic probes of function. Cell-permeable small molecules, however, generally do not exploit these targets, owing to the difficulty in the design of high affinity, specific small molecules targeting RNA. As part of...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb400265y

    authors: Rzuczek SG,Gao Y,Tang ZZ,Thornton CA,Kodadek T,Disney MD

    更新日期:2013-10-18 00:00:00

  • Conformational dynamics of a regulator of G-protein signaling protein reveals a mechanism of allosteric inhibition by a small molecule.

    abstract::Regulators of G protein signaling (RGS) proteins are key players in regulating signaling via G protein-coupled receptors. RGS proteins directly bind to the Gα-subunits of activated heterotrimeric G-proteins, and accelerate the rate of GTP hydrolysis, thereby rapidly deactivating G-proteins. Using atomistic simulations...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb400568g

    authors: Vashisth H,Storaska AJ,Neubig RR,Brooks CL 3rd

    更新日期:2013-12-20 00:00:00

  • Small-molecule-modified surfaces engage cells through the αvβ3 integrin.

    abstract::Integrins play myriad and vital roles in development and disease. They connect a cell with its surroundings and transmit chemical and mechanical signals across the plasma membrane to the cell's interior. Dissecting their roles in cell behavior is complicated by their overlapping ligand specificity and shared downstrea...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb2004725

    authors: Klim JR,Fowler AJ,Courtney AH,Wrighton PJ,Sheridan RT,Wong ML,Kiessling LL

    更新日期:2012-03-16 00:00:00

  • Iron Uptake Oxidoreductase (IruO) Uses a Flavin Adenine Dinucleotide Semiquinone Intermediate for Iron-Siderophore Reduction.

    abstract::Many pathogenic bacteria including Staphylococcus aureus use iron-chelating siderophores to acquire iron. Iron uptake oxidoreductase (IruO), a flavin adenine dinucleotide (FAD)-containing nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reductase from S. aureus, functions as a reductase for IsdG and IsdI,...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.7b00203

    authors: Kobylarz MJ,Heieis GA,Loutet SA,Murphy MEP

    更新日期:2017-07-21 00:00:00

  • Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists.

    abstract::The inhibitor of apoptosis (IAP) proteins are critical regulators of cancer cell survival, which makes them attractive targets for therapeutic intervention in cancers. Herein, we describe the structure-based design of IAP antagonists with high affinities and selectivity (>2000-fold) for c-IAP1 over XIAP and their func...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb900083m

    authors: Ndubaku C,Varfolomeev E,Wang L,Zobel K,Lau K,Elliott LO,Maurer B,Fedorova AV,Dynek JN,Koehler M,Hymowitz SG,Tsui V,Deshayes K,Fairbrother WJ,Flygare JA,Vucic D

    更新日期:2009-07-17 00:00:00

  • Small Molecule Phenotypic Screen Identifies Novel Regulators of LDLR Expression.

    abstract::Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. The current treatment options for AD are limited to ameliorating cognitive decline temporarily and not reversing or preventing the progression of dementia. Hence, more effective therapeutic strategies are needed ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.0c00851

    authors: Krishnan N,Chen X,Donnelly-Roberts D,Mohler EG,Holtzman DM,Gopalakrishnan SM

    更新日期:2020-12-18 00:00:00

  • Selective small molecule probes for the hypoxia inducible factor (HIF) prolyl hydroxylases.

    abstract::The hypoxia inducible factor (HIF) system is central to the signaling of low oxygen (hypoxia) in animals. The levels of HIF-α isoforms are regulated in an oxygen-dependent manner by the activity of the HIF prolyl-hydroxylases (PHD or EGLN enzymes), which are Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases. Here, ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb400088q

    authors: Chowdhury R,Candela-Lena JI,Chan MC,Greenald DJ,Yeoh KK,Tian YM,McDonough MA,Tumber A,Rose NR,Conejo-Garcia A,Demetriades M,Mathavan S,Kawamura A,Lee MK,van Eeden F,Pugh CW,Ratcliffe PJ,Schofield CJ

    更新日期:2013-07-19 00:00:00

  • Retroviral display in gene therapy, protein engineering, and vaccine development.

    abstract::The display and analysis of proteins expressed on biological surfaces has become an attractive tool for the study of molecular interactions in enzymology, protein engineering, and high-throughput screening. Among the growing number of established display systems, retroviruses offer a unique and fully mammalian platfor...

    journal_title:ACS chemical biology

    pub_type: 杂志文章,评审

    doi:10.1021/cb100285n

    authors: Urban JH,Merten CA

    更新日期:2011-01-21 00:00:00

  • Structural and Functional Basis of C-Methylation of Coumarin Scaffolds by NovO.

    abstract::C-methylation of aromatic small molecules by C-methyltransferases (C-MTs) is an important biological transformation that involves C-C bond formation using S-adenosyl-l-methionine (SAM) as the methyl donor. Here, two advances in the mechanistic understanding of C-methylation of the 8-position of coumarin substrates cat...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.6b01053

    authors: Sadler JC,Chung CH,Mosley JE,Burley GA,Humphreys LD

    更新日期:2017-02-17 00:00:00

  • CRISPRi and CRISPRa Screens in Mammalian Cells for Precision Biology and Medicine.

    abstract::Next-generation DNA sequencing technologies have led to a massive accumulation of genomic and transcriptomic data from patients and healthy individuals. The major challenge ahead is to understand the functional significance of the elements of the human genome and transcriptome, and implications for diagnosis and treat...

    journal_title:ACS chemical biology

    pub_type: 杂志文章,评审

    doi:10.1021/acschembio.7b00657

    authors: Kampmann M

    更新日期:2018-02-16 00:00:00

  • Development of a Protease Biosensor Based on a Dimerization-Dependent Red Fluorescent Protein.

    abstract::Dysregulated activity of the protease matriptase is a key contributor to aggressive tumor growth, cancer metastasis, and osteoarthritis. Methods for the detection and quantification of matriptase activity and inhibition would be useful tools. To address this need, we developed a matriptase-sensitive protein biosensor ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.7b00715

    authors: Mitchell AC,Alford SC,Hunter SA,Kannan D,Parra Sperberg RA,Chang CH,Cochran JR

    更新日期:2018-01-19 00:00:00

  • Interrogating Key Positions of Size-Reduced TALE Repeats Reveals a Programmable Sensor of 5-Carboxylcytosine.

    abstract::Transcription-activator-like effector (TALE) proteins consist of concatenated repeats that recognize consecutive canonical nucleobases of DNA via the major groove in a programmable fashion. Since this groove displays unique chemical information for the four human epigenetic cytosine nucleobases, TALE repeats with epig...

    journal_title:ACS chemical biology

    pub_type: 信件

    doi:10.1021/acschembio.6b00627

    authors: Maurer S,Giess M,Koch O,Summerer D

    更新日期:2016-12-16 00:00:00

  • Discovery of a nitric oxide responsive quorum sensing circuit in Vibrio harveyi.

    abstract::Bacteria use small molecules to assess the density and identity of nearby organisms and formulate a response. This process, called quorum sensing (QS), commonly regulates bioluminescence, biofilm formation, and virulence. Vibrio harveyi have three described QS circuits. Each involves the synthesis of a molecule that r...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb300215t

    authors: Henares BM,Higgins KE,Boon EM

    更新日期:2012-08-17 00:00:00

  • Role of pseudouridine in structural rearrangements of helix 69 during bacterial ribosome assembly.

    abstract::As part of the central core domain of the ribosome, helix 69 of 23S rRNA participates in an important intersubunit bridge and contacts several protein translation factors. Helix 69 is believed to play key roles in protein synthesis. Even though high-resolution crystal structures of the ribosome exist, the solution dyn...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb200497q

    authors: Sakakibara Y,Chow CS

    更新日期:2012-05-18 00:00:00

  • Recruitment and Regulation of the Non-ribosomal Peptide Synthetase Modifying Cytochrome P450 Involved in Nikkomycin Biosynthesis.

    abstract::The β-hydroxylation of l-histidine is the first step in the biosynthesis of the imidazolone base of the antifungal drug nikkomycin. The cytochrome P450 (NikQ) hydroxylates the amino acid while it is appended via a phosphopantetheine linker to the non-ribosomal peptide synthetase (NRPS) NikP1. The latter enzyme is comp...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.7b00081

    authors: Wise CE,Makris TM

    更新日期:2017-05-19 00:00:00

  • Furoxan Nitric Oxide Donors Disperse Pseudomonas aeruginosa Biofilms, Accelerate Growth, and Repress Pyoverdine Production.

    abstract::The use of nitric oxide (NO) as a signal for biofilm dispersal has been shown to increase the susceptibility of many biofilms to antibiotics, promoting their eradication. The delivery of NO to biofilms can be achieved by using NO donors with different kinetics and properties of NO release that can influence their effi...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.7b00256

    authors: Poh WH,Barraud N,Guglielmo S,Lazzarato L,Rolando B,Fruttero R,Rice SA

    更新日期:2017-08-18 00:00:00

  • How many antimicrobial peptide molecules kill a bacterium? The case of PMAP-23.

    abstract::Antimicrobial peptides (AMPs) kill bacteria mainly through the perturbation of their membranes and are promising compounds to fight drug resistance. Models of the mechanism of AMPs-induced membrane perturbation were developed based on experiments in liposomes, but their relevance for bacterial killing is debated. We d...

    journal_title:ACS chemical biology

    pub_type: 信件

    doi:10.1021/cb500426r

    authors: Roversi D,Luca V,Aureli S,Park Y,Mangoni ML,Stella L

    更新日期:2014-09-19 00:00:00