Abstract:
: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.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Tomita T,Kim SY,Teramoto K,Meguro A,Ozaki T,Yoshida A,Motoyoshi Y,Mori N,Ishigami K,Watanabe H,Nishiyama M,Kuzuyama Tdoi
10.1021/acschembio.7b00154subject
Has Abstractpub_date
2017-06-16 00:00:00pages
1621-1628issue
6eissn
1554-8929issn
1554-8937journal_volume
12pub_type
杂志文章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
更新日期:2012-07-20 00:00:00
abstract::Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drug...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00493
更新日期:2017-10-20 00:00:00
abstract::Generating highly selective probes to interrogate protein kinase function in biological studies remains a challenge, and new strategies are required. Herein, we describe the development of the first highly selective and cell-permeable inhibitor of c-Src, a key signaling kinase in cancer. Our strategy involves extensio...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb300172e
更新日期:2012-08-17 00:00:00
abstract::Stapled peptides have great potential as modulators of protein-protein interactions (PPIs). However, there is a vast landscape of chemical features that can be varied for any given peptide, and identifying a set of features that maximizes cellular uptake and subsequent target engagement remains a key challenge. Herein...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.9b00063
更新日期:2019-03-15 00:00:00
abstract::MbtA is an adenylating enzyme from Mycobacterium tuberculosis that catalyzes the first step in the biosynthesis of the mycobactins. A bisubstrate inhibitor of MbtA (Sal-AMS) was previously described that displays potent antitubercular activity under iron-replete as well as iron-deficient growth conditions. This findin...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb300112x
更新日期:2012-10-19 00:00:00
abstract::Determining the impact of lipid electrophile-mediated protein damage that occurs during oxidative stress requires a comprehensive analysis of electrophile targets adducted under pathophysiological conditions. Incorporation of ω-alkynyl linoleic acid into the phospholipids of macrophages prior to activation by Kdo2-lip...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00480
更新日期:2017-08-18 00:00:00
abstract::Hydrogen sulfide (H2S) is an important gasotransmitter and biomolecule, and many synthetic small-molecule H2S donors have been developed for H2S-related research. One important class of triggerable H2S donors is self-immolative thiocarbamates, which function by releasing carbonyl sulfide (COS), which is rapidly conver...
journal_title:ACS chemical biology
pub_type: 信件
doi:10.1021/acschembio.8b00981
更新日期:2019-02-15 00:00:00
abstract::Protein organization on biomembranes and their dynamics are essential for cellular function. It is not clear, however, how protein binding may influence the assembly of underlying lipids or how the membrane structure leads to functional protein organization. Toward this goal, we investigated the effects of annexin a5 ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb900303s
更新日期:2010-04-16 00:00:00
abstract::The nematode Caenorhabditis elegans is an excellent model organism for studies of glycan dynamics, a goal that requires tools for imaging glycans in vivo. Here we applied the bioorthogonal chemical reporter technique for the molecular imaging of mucin-type O-glycans in live C. elegans. We treated worms with azidosugar...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb900254y
更新日期:2009-12-18 00:00:00
abstract::RNAs are involved in interaction networks with other biomolecules and are crucial for proper cell function. Yet their biochemical analysis remains challenging. For Förster Resonance Energy Transfer (FRET), a common tool to study such interaction networks, two interacting molecules have to be fluorescently labeled. "Sp...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00332
更新日期:2017-12-15 00:00:00
abstract::Engineering gene circuits with novel functions holds promise for broad applications in biology, engineering, and medicine. Directed evolution complements rational design as an important strategy for optimizing gene circuits and circuit elements. ...
journal_title:ACS chemical biology
pub_type: 评论,杂志文章,评审
doi:10.1021/cb6004596
更新日期:2006-12-20 00:00:00
abstract::Understanding the ways in which pathogens invade and neutralize their hosts is of great interest from both an academic and a clinical perspective. However, in many cases genetic tools are unavailable or insufficient to fully characterize the detailed mechanisms of pathogenesis. Small molecule approaches are particular...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb9001409
更新日期:2009-08-21 00:00:00
abstract::Our immune system constantly samples peptides found inside the body as a means to detect foreign pathogens, infected cells, and tumorous cells. T cells, which carry out the critical task of distinguishing self from nonself peptides, can only survey peptides that are presented by the major histocompatibility complex pr...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb400594q
更新日期:2013-11-15 00:00:00
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
更新日期:2018-01-19 00:00:00
abstract::Human alkyladenine DNA glycosylase (AAG) initiates the base excision repair pathway by excising alkylated and deaminated purine lesions. In vitro biochemical experiments demonstrate that AAG uses facilitated diffusion to efficiently search DNA to find rare sites of damage and suggest that electrostatic interactions ar...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b00409
更新日期:2015-11-20 00:00:00
abstract::In eukaryotic cells, proteins and RNAs are transported between the nucleus and the cytoplasm by nuclear import and export receptors. Over the past decade, small molecules that inhibit the nuclear export receptor CRM1 have been identified, most notably leptomycin B. However, up to now no small molecule inhibitors of nu...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb100094k
更新日期:2010-10-15 00:00:00
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
更新日期:2020-12-18 00:00:00
abstract::Diversity of scaffold structure and function is a hallmark of the >50,000 isoprenoid natural products such as taxol. Whereas most members of this class are assembled by iterative head-to-tail enzymatic joining reactions between delta2- and delta3-isopentenyl diphosphate (IPP) monomers, dimerization of two delta2-IPP m...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb700094s
更新日期:2007-05-22 00:00:00
abstract::Ineffective cellular delivery is a common problem in numerous biological applications. Developing delivery reagents that work robustly in a variety of experimental settings remains a challenge. Herein, we report how peptides derived from the prototypical cell penetrating peptide TAT can be used in combination with a s...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.9b00585
更新日期:2019-12-20 00:00:00
abstract::Thermodynamics and kinetics of protein-ligand binding are both important aspects for the design of novel drug molecules. Presently, thermodynamic data are collected with isothermal titration calorimetry, while kinetic data are mostly derived from surface plasmon resonance. The new method of kinITC provides both thermo...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.9b00895
更新日期:2020-03-20 00:00:00
abstract::FAT10 is a ubiquitin-like protein suggested to target proteins for proteasomal degradation. It is highly upregulated upon pro-inflammatory cytokines, namely, TNFα, IFNγ, and IL6, and was found to be highly expressed in various epithelial cancers. Evidence suggests that FAT10 is involved in cancer development and may h...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.9b00667
更新日期:2019-12-20 00:00:00
abstract::We have developed a chemically controlled very long-acting delivery system to support once-monthly administration of a peptidic GLP-1R agonist. Initially, the prototypical GLP-1R agonist exenatide was covalently attached to hydrogel microspheres by a self-cleaving β-eliminative linker; after subcutaneous injection in ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00218
更新日期:2017-08-18 00:00:00
abstract::The mitochondrial ADP/ATP carrier (AAC) is a prominent actor in the energetic regulation of the cell, importing ADP into the mitochondria and exporting ATP toward the cytoplasm. Severe genetic diseases have been ascribed to specific mutations in this membrane protein. How minute, well-localized modifications of the tr...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb300012j
更新日期:2012-07-20 00:00:00
abstract::Drug optimization is guided by biophysical methods with increasing popularity. In the context of lead structure modifications, the introduction of methyl groups is a simple but potentially powerful approach. Hence, it is crucial to systematically investigate the influence of ligand methylation on biophysical character...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.9b00476
更新日期:2019-12-20 00:00:00
abstract::Nearly one-third of the encoded proteome is comprised of secretory proteins that enable communication between cells and organ systems, playing a ubiquitous role in human health and disease. High-throughput detection of secreted proteins would enhance efforts to identify therapies for secretion-related diseases. Using ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.9b00001
更新日期:2019-03-15 00:00:00
abstract::Plasmodium falciparum thymidylate synthase-dihydrofolate reductase (TS-DHFR) is an essential enzyme in folate biosynthesis and a major malarial drug target. This bifunctional enzyme thus presents different design approaches for developing novel inhibitors against drug-resistant mutants. We performed a high-throughput ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb8002804
更新日期:2009-01-16 00:00:00
abstract::The goal of incorporating renewable carbon into the fuel and chemical enterprise will most likely be successful when combined systems of biocatalysts and chemical catalysts are exploited. Significant efforts in the biocatalytic release of sugars from biomass are being pursued for subsequent use in fermentation. Two re...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb7001522
更新日期:2007-08-17 00:00:00
abstract::The arabinosyltransferases responsible for the biosynthesis of the arabinan domains of two abundant heteropolysaccharides of the cell envelope of all mycobacterial species, lipoarabinomannan and arabinogalactan, are validated drug targets. Using a cell envelope preparation from Mycobacterium smegmatis as the enzyme so...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.6b00093
更新日期:2016-06-17 00:00:00
abstract::The ATP site of kinases displays remarkable conformational flexibility when accommodating chemically diverse small molecule inhibitors. The so-called activation segment, whose conformation controls catalytic activity and access to the substrate binding pocket, can undergo a large conformational change with the active ...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb500129t
更新日期:2014-06-20 00:00:00
abstract::APOBEC3G is a single-stranded DNA cytosine deaminase that comprises part of the innate immune response to viruses and transposons. Although APOBEC3G is the prototype for understanding the larger mammalian polynucleotide deaminase family, no specific chemical inhibitors exist to modulate its activity. High-throughput s...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb200440y
更新日期:2012-03-16 00:00:00