Structural Insights into the CotB2-Catalyzed Cyclization of Geranylgeranyl Diphosphate to the Diterpene Cyclooctat-9-en-7-ol.


:The diterpene cyclase CotB2 catalyzes the cyclization of geranylgeranyl diphosphate (GGPP) to the tricyclic cyclooctat-9-en-7-ol, which is characterized by a 5-8-5-fused ring skeleton. We have previously proposed a cyclization cascade involving a unique carbon-carbon bond rearrangement combined with multiple hydride shifts, all occurring at a single active site. Here, we report the first high-resolution X-ray crystal structure of CotB2 with bound substrate analog geranylgeranyl thiodiphosphate (GGSPP). In the GGSPP-bound form, GGSPP folds into a unique S-shaped conformation that probably reflects the substrate-bound state prior to ionization of the substrate GGPP. The folded framework of GGSPP is surrounded by hydrophobic residues and several aromatic and asparagine residues that are well-positioned to stabilize a series of reactive carbocation intermediates through a combination of cation-π and dipole charge interactions. The combined crystal structures and mutagenesis-based biochemical assays provide a structural basis for exquisite control of ring formation and stereochemistry during CotB2 catalysis.


ACS Chem Biol


ACS chemical biology


Tomita T,Kim SY,Teramoto K,Meguro A,Ozaki T,Yoshida A,Motoyoshi Y,Mori N,Ishigami K,Watanabe H,Nishiyama M,Kuzuyama T




Has Abstract


2017-06-16 00:00:00












  • Mechanism-Based Post-Translational Modification and Inactivation in Terpene Synthases.

    abstract::Terpenes are ubiquitous natural chemicals with diverse biological functions spanning all three domains of life. In specialized metabolism, the active sites of terpene synthases (TPSs) evolve in shape and reactivity to direct the biosynthesis of a myriad of chemotypes for organismal fitness. As most terpene biosynthesi...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Kersten RD,Diedrich JK,Yates JR 3rd,Noel JP

    更新日期:2015-11-20 00:00:00

  • Pentamycin Biosynthesis in Philippine Streptomyces sp. S816: Cytochrome P450-Catalyzed Installation of the C-14 Hydroxyl Group.

    abstract::Pentamycin is a polyene antibiotic, registered in Switzerland for the treatment of vaginal candidiasis, trichomoniasis, and mixed infections. Chemical instability has hindered its widespread application and development as a drug. Here, we report the identification of Streptomyces sp. S816, isolated from Philippine man...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Zhou S,Song L,Masschelein J,Sumang FAM,Papa IA,Zulaybar TO,Custodio AB,Zabala D,Alcantara EP,de Los Santos ELC,Challis GL

    更新日期:2019-06-21 00:00:00

  • Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry.

    abstract::Recent advances in understanding the relevance of noncoding RNA (ncRNA) to disease have increased interest in drugging ncRNA with small molecules. The recent discovery of ribocil, a structurally distinct synthetic mimic of the natural ligand of the flavin mononucleotide (FMN) riboswitch, has revealed the potential che...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Rizvi NF,Howe JA,Nahvi A,Klein DJ,Fischmann TO,Kim HY,McCoy MA,Walker SS,Hruza A,Richards MP,Chamberlin C,Saradjian P,Butko MT,Mercado G,Burchard J,Strickland C,Dandliker PJ,Smith GF,Nickbarg EB

    更新日期:2018-03-16 00:00:00

  • Design of cyclic peptides that bind protein surfaces with antibody-like affinity.

    abstract::There is a pressing need for new molecular tools to target protein surfaces with high affinity and specificity. Here, we describe cyclic messenger RNA display with a trillion-member covalent peptide macrocycle library. Using this library, we have designed a number of high-affinity, redox-insensitive, cyclic peptides t...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Millward SW,Fiacco S,Austin RJ,Roberts RW

    更新日期:2007-09-21 00:00:00

  • Adversarial Controls for Scientific Machine Learning.

    abstract::New machine learning methods to analyze raw chemical and biological data are now widely accessible as open-source toolkits. This positions researchers to leverage powerful, predictive models in their own domains. We caution, however, that the application of machine learning to experimental research merits careful cons...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Chuang KV,Keiser MJ

    更新日期:2018-10-19 00:00:00

  • Identification of potent phosphodiesterase inhibitors that demonstrate cyclic nucleotide-dependent functions in apicomplexan parasites.

    abstract::Apicomplexan parasites, including Plasmodium falciparum and Toxoplasma gondii, the causative agents of severe malaria and toxoplasmosis, respectively, undergo several critical developmental transitions during their lifecycle. Most important for human pathogenesis is the asexual cycle, in which parasites undergo rounds...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Howard BL,Harvey KL,Stewart RJ,Azevedo MF,Crabb BS,Jennings IG,Sanders PR,Manallack DT,Thompson PE,Tonkin CJ,Gilson PR

    更新日期:2015-04-17 00:00:00

  • Acetyltransferase p300/CBP associated Factor (PCAF) regulates crosstalk-dependent acetylation of histone H3 by distal site recognition.

    abstract::Epigenetic regulation is directed, in part, by the correlated placement of histone post-translational modifications, but the mechanisms controlling correlated modifications are incompletely understood. Correlations arise from crosstalk among modifications and are frequently attributed to protein-protein interactions t...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Kornacki JR,Stuparu AD,Mrksich M

    更新日期:2015-01-16 00:00:00

  • ATP-mediated kinome selectivity: the missing link in understanding the contribution of individual JAK Kinase isoforms to cellular signaling.

    abstract::Kinases constitute an important class of therapeutic targets being explored both by academia and the pharmaceutical industry. The major focus of this effort was directed toward the identification of ATP competitive inhibitors. Although it has long been recognized that the intracellular concentration of ATP is very dif...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Thorarensen A,Banker ME,Fensome A,Telliez JB,Juba B,Vincent F,Czerwinski RM,Casimiro-Garcia A

    更新日期:2014-07-18 00:00:00

  • HIV protease inhibitors block streptolysin S production.

    abstract::Streptolysin S (SLS) is a post-translationally modified peptide cytolysin that is produced by the human pathogen Streptococcus pyogenes. SLS belongs to a large family of azole-containing natural products that are biosynthesized via an evolutionarily conserved pathway. SLS is an important virulence factor during S. pyo...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Maxson T,Deane CD,Molloy EM,Cox CL,Markley AL,Lee SW,Mitchell DA

    更新日期:2015-05-15 00:00:00

  • Characterization of Class IB Terpene Synthase: The First Crystal Structure Bound with a Substrate Surrogate.

    abstract::Terpene synthases (TS) are classified into two broad types, Class I and II, based on the chemical strategy for initial carbocation formation and motif sequences of the catalytic site. We have recently identified a new class of enzymes, Class IB, showing the acceptability of long (C20-C35) prenyl-diphosphates as substr...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Stepanova R,Inagi H,Sugawara K,Asada K,Nishi T,Ueda D,Yasuno Y,Shinada T,Miki K,Fujihashi M,Sato T

    更新日期:2020-06-19 00:00:00

  • Boron dipyrromethene as a fluorescent caging group for single-photon uncaging with long-wavelength visible light.

    abstract::Caged compounds are useful tools for precise spatiotemporal modulation of cell functions, but in most cases uncaging requires ultraviolet (UV) light, which is cytotoxic and has limited tissue penetration. Therefore, caged compounds that can be activated by longer-wavelength light are required. Here we describe a novel...

    journal_title:ACS chemical biology

    pub_type: 信件


    authors: Umeda N,Takahashi H,Kamiya M,Ueno T,Komatsu T,Terai T,Hanaoka K,Nagano T,Urano Y

    更新日期:2014-10-17 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


    authors: Wise CE,Makris TM

    更新日期:2017-05-19 00:00:00

  • Multiple Chemical Inducible Tal Effectors for Genome Editing and Transcription Activation.

    abstract::Inducible modulation is often required for precise investigations and manipulations of dynamic biological processes. Transcription activator-like effectors (TALEs) provide a powerful tool for targeted gene editing and transcriptional programming. We designed a series of chemical inducible systems by coupling TALEs wit...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Zhao C,Zhang Y,Zhao Y,Ying Y,Ai R,Zhang J,Wang Y

    更新日期:2018-03-16 00:00:00

  • Chemical detoxification of small molecules by Caenorhabditis elegans.

    abstract::Caenorhabditis elegans lives in compost and decaying fruit, eats bacteria and is exposed to pathogenic microbes. We show that C. elegans is able to modify diverse microbial small-molecule toxins via both O- and N-glucosylation as well as unusual 3'-O-phosphorylation of the resulting glucosides. The resulting glucosyla...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Stupp GS,von Reuss SH,Izrayelit Y,Ajredini R,Schroeder FC,Edison AS

    更新日期:2013-02-15 00:00:00

  • Covalent-Fragment Screening of BRD4 Identifies a Ligandable Site Orthogonal to the Acetyl-Lysine Binding Sites.

    abstract::BRD4, a member of the bromodomain and extraterminal domain (BET) family, has emerged as a promising epigenetic target in cancer and inflammatory disorders. All reported BET family ligands bind within the bromodomain acetyl-lysine binding sites and competitively inhibit BET protein interaction with acetylated chromatin...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Olp MD,Sprague DJ,Goetz CJ,Kathman SG,Wynia-Smith SL,Shishodia S,Summers SB,Xu Z,Statsyuk AV,Smith BC

    更新日期:2020-04-17 00:00:00

  • Molecular tweezers inhibit islet amyloid polypeptide assembly and toxicity by a new mechanism.

    abstract::In type-2 diabetes (T2D), islet amyloid polypeptide (IAPP) self-associates into toxic assemblies causing islet β-cell death. Therefore, preventing IAPP toxicity is a promising therapeutic strategy for T2D. The molecular tweezer CLR01 is a supramolecular tool for selective complexation of K residues in (poly)peptides. ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Lopes DH,Attar A,Nair G,Hayden EY,Du Z,McDaniel K,Dutt S,Bravo-Rodriguez K,Mittal S,Klärner FG,Wang C,Sanchez-Garcia E,Schrader T,Bitan G

    更新日期:2015-06-19 00:00:00

  • In vitro selection of anti-Akt2 thioether-macrocyclic peptides leading to isoform-selective inhibitors.

    abstract::The Akt kinase family, consisting of three isoforms in humans, is a well-validated class of drug target. Through various screening campaigns in academics and pharmaceutical industries, several promising inhibitors have been developed to date. However, due to the mechanistic and structural similarities of Akt kinases, ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Hayashi Y,Morimoto J,Suga H

    更新日期:2012-03-16 00:00:00

  • Biochemical and biophysical analysis of a chiral PqsD inhibitor revealing tight-binding behavior and enantiomers with contrary thermodynamic signatures.

    abstract::Antivirulence strategies addressing bacterial pathogenicity without exhibiting growth inhibition effects represent a novel approach to overcome today's crisis in antibiotic development. In recent studies, we examined various inhibitors of PqsD, an enzyme involved in formation of Pseudomonas aeruginosa cell-to-cell sig...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Storz MP,Brengel C,Weidel E,Hoffmann M,Hollemeyer K,Steinbach A,Müller R,Empting M,Hartmann RW

    更新日期:2013-12-20 00:00:00

  • Small Molecule Inhibitors of Human DNA Polymerase λ.

    abstract::To discover chemical probes to further under-stand the function of individual DNA polymerases, we established a generally applicable high-throughput screening. By applying this technique we discovered three novel inhibitor classes of human DNA polymerase λ (DNA Pol λ), a key enzyme to maintain the genetic integrity of...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Strittmatter T,Bareth B,Immel TA,Huhn T,Mayer TU,Marx A

    更新日期:2011-04-15 00:00:00

  • Iterative Focused Screening with Biological Fingerprints Identifies Selective Asc-1 Inhibitors Distinct from Traditional High Throughput Screening.

    abstract::N-methyl-d-aspartate receptors (NMDARs) mediate glutamatergic signaling that is critical to cognitive processes in the central nervous system, and NMDAR hypofunction is thought to contribute to cognitive impairment observed in both schizophrenia and Alzheimer's disease. One approach to enhance the function of NMDAR is...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Kutchukian PS,Warren L,Magliaro BC,Amoss A,Cassaday JA,O'Donnell G,Squadroni B,Zuck P,Pascarella D,Culberson JC,Cooke AJ,Hurzy D,Schlegel KS,Thomson F,Johnson EN,Uebele VN,Hermes JD,Parmentier-Batteur S,Finley M

    更新日期:2017-02-17 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


    authors: Schapira M

    更新日期:2016-03-18 00:00:00

  • Thymoquinone blocks pSer/pThr recognition by Plk1 Polo-box domain as a phosphate mimic.

    abstract::Phosphorylation-dependent protein-protein interaction has rarely been targeted in medicinal chemistry. Thymoquinone, a naturally occurring antitumor agent, disrupts prephosphorylated substrate recognition by the polo-box domain of polo-like kinase 1, a key mitotic regulator responsible for various carcinogenesis when ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Yin Z,Song Y,Rehse PH

    更新日期:2013-02-15 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


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

    更新日期:2017-02-17 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


    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

  • Design, synthesis, and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs.

    abstract::Designed second mitochondrial activator of caspases (Smac) mimetics based on an accessible [7,5]-bicyclic scaffold bind to and antagonize protein interactions involving the inhibitor of apoptosis (IAP) proteins, X-chromosome-linked IAP (XIAP), melanoma IAP (ML-IAP), and c-IAPs 1 and 2 (cIAP1 and cIAP2). The design rat...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Zobel K,Wang L,Varfolomeev E,Franklin MC,Elliott LO,Wallweber HJ,Okawa DC,Flygare JA,Vucic D,Fairbrother WJ,Deshayes K

    更新日期:2006-09-19 00:00:00

  • Douglas Weibel: using microfluidics for microbiology.

    abstract::The ubiquity of microorganisms is unparalleled in any other known organism. These creatures surround our outsides and colonize our insides, a fact that has been known for centuries. However, despite their prevalence and long study, many of their characteristics still remain largely unexplained, including how proteins ...

    journal_title:ACS chemical biology

    pub_type: 传,历史文章,杂志文章


    authors: Brownlee C

    更新日期:2010-07-16 00:00:00

  • Fluorescent Chemosensors as Future Tools for Cancer Biology.

    abstract::It is well established that aberrant cellular biochemical activity is strongly linked to the formation and progression of various cancers. Assays that could aid in cancer diagnostics, assessing anticancer drug resistance, and in the discovery of new anticancer drugs are highly warranted. In recent years, a large numbe...

    journal_title:ACS chemical biology

    pub_type: 杂志文章,评审


    authors: Singh K,Rotaru AM,Beharry AA

    更新日期:2018-07-20 00:00:00

  • A Multimodal Ca(II) Responsive Near IR-MR Contrast Agent Exhibiting High Cellular Uptake.

    abstract::Ca(II) ions are critical for the proper function of neurons by contributing to synaptic signaling and regulating neuronal plasticity. Dysregulation of Ca(II) is associated with a number of pathologies that cause neurodegeneration; therefore the ability to monitor Ca(II) intracellularly is an important target for molec...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Adams CJ,Krueger R,Meade TJ

    更新日期:2020-02-21 00:00:00

  • Rheostatic Control of Cas9-Mediated DNA Double Strand Break (DSB) Generation and Genome Editing.

    abstract::We recently reported two novel tools for precisely controlling and quantifying Cas9 activity: a chemically inducible Cas9 variant (ciCas9) that can be rapidly activated by small molecules and a ddPCR assay for time-resolved measurement of DNA double strand breaks (DSB-ddPCR). Here, we further demonstrate the potential...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Rose JC,Stephany JJ,Wei CT,Fowler DM,Maly DJ

    更新日期:2018-02-16 00:00:00

  • Revisiting the role of glycosylation in the structure of human IgG Fc.

    abstract::Binding of the Fc domain of Immunoglobulin G (IgG) to Fcγ receptors on leukocytes can initiate a series of signaling events resulting in antibody-dependent cell-mediated cytotoxicity (ADCC) and other important immune responses. Fc domains lacking glycosylation at N297 have greatly diminished Fcγ receptor binding and l...

    journal_title:ACS chemical biology

    pub_type: 杂志文章


    authors: Borrok MJ,Jung ST,Kang TH,Monzingo AF,Georgiou G

    更新日期:2012-09-21 00:00:00