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 are critical to the searching process. However, it remains an open question whether DNA searching limits the rate of DNA repair in vivo. We constructed AAG mutants with altered searching ability and measured their ability to protect yeast from alkylation damage in order to address this question. Each of the conserved arginine and lysine residues that are near the DNA binding interface were mutated, and the functional impacts were evaluated using kinetic and thermodynamic analysis. These mutations do not perturb catalysis of N-glycosidic bond cleavage, but they decrease the ability to capture rare lesion sites. Nonspecific and specific DNA binding properties are closely correlated, suggesting that the electrostatic interactions observed in the specific recognition complex are similarly important for DNA searching complexes. The ability of the mutant proteins to complement repair-deficient yeast cells is positively correlated with the ability of the proteins to search DNA in vitro, suggesting that cellular resistance to DNA alkylation is governed by the ability to find and efficiently capture cytotoxic lesions. It appears that chromosomal access is not restricted and toxic sites of alkylation damage are readily accessible to a searching protein.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Zhang Y,O'Brien PJdoi
10.1021/acschembio.5b00409subject
Has Abstractpub_date
2015-11-20 00:00:00pages
2606-15issue
11eissn
1554-8929issn
1554-8937journal_volume
10pub_type
杂志文章abstract：:Enzymatic plasticity, as a modern term referring to the functional conversion of an enzyme, is significant for enzymatic activity redesign. The bacterial diterpene cyclase CotB2 is a typical plastic enzyme by which its native form precisely conducts a chemical reaction while its mutants diversify the catalytic functio...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.0c00645
更新日期：2020-10-16 00:00:00
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
更新日期：2012-05-18 00:00:00
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
doi：10.1021/cb501004q
更新日期：2015-04-17 00:00:00
abstract：:The LpxC enzyme in the lipid A biosynthetic pathway is one of the most promising and clinically unexploited antibiotic targets for treatment of multidrug-resistant Gram-negative infections. Progress in medicinal chemistry has led to the discovery of potent LpxC inhibitors with a variety of chemical scaffolds and disti...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb400067g
更新日期：2014-01-17 00:00:00
abstract：:Nature uses four methods of carbon chain elongation for the production of 2-ketoacids, fatty acids, polyketides, and isoprenoids. Using a combination of quantum mechanical (QM) modeling, protein-substrate modeling, and protein and metabolic engineering, we have engineered the enzymes involved in leucine biosynthesis f...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb200313e
更新日期：2012-04-20 00:00:00
abstract：:Angiogenesis, the formation of new blood vessels, is implicated in a number of important human diseases, including cancer, diabetic retinopathy, and rheumatoid arthritis. To identify clinically useful angiogenesis inhibitors, we assembled and screened a library of mostly Food and Drug Administration-approved drugs for...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb600362d
更新日期：2007-04-24 00:00:00
abstract：:Replacing the two Mn(2+) ions normally present in human Arginase I with Co(2+) resulted in a significantly lowered K(M) value without a concomitant reduction in k(cat). In addition, the pH dependence of the reaction was shifted from a pK(a) of 8.5 to a pK(a) of 7.5. The combination of these effects led to a 10-fold in...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb900267j
更新日期：2010-03-19 00:00:00
abstract：:Photoinduced cross-linking (PIC) has become a powerful tool in chemical biology for the identification and mapping of stable or transient interactions between biomacromolecules and their (unknown) ligands. However, the value of PIC for in vitro and in vivo structural proteomics can be realized only if cross-linking re...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb400731s
更新日期：2014-03-21 00:00:00
abstract：:Lasso peptides are bacterial ribosomally synthesized and post-translationally modified peptides. They have sparked increasing interest in peptide-based drug development because of their compact, interlocked structure, which offers superior stability and protein-binding capacity. Disulfide bond-containing lasso peptide...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.5b00584
更新日期：2015-11-20 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：: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：:Leishmaniases affect the poorest people on earth and have no effective drug therapy. Here, we present the crystal structure of the mitochondrial isoform of class I fumarate hydratase (FH) from Leishmania major and compare it to the previously determined cytosolic Leishmania major isoform. We further describe the mecha...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.8b00972
更新日期：2019-02-15 00:00:00
abstract：:New technology for the derivatization of peptide natural products is required for drug development. Despite the recent advances in the genome sequencing technique enabling us to search for the biosynthetic genes for wide variety of natural products, the technical methods to get access to them are limited. A class of R...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.9b00330
更新日期：2019-06-21 00:00:00
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
更新日期：2018-02-16 00:00:00
abstract：:Developing computational tools for a chassis-centered biosynthetic pathway design is very important for a productive heterologous biosynthesis system by considering enormous foreign biosynthetic reactions. For many cases, a pathway to produce a target molecule consists of both native and heterologous reactions when ut...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.7b00605
更新日期：2017-11-17 00:00:00
abstract：:A complication of diabetes is the inability of wounds to heal in diabetic patients. Diabetic wounds are refractory to healing due to the involvement of activated matrix metalloproteinases (MMPs), which remodel the tissue resulting in apoptosis. There are no readily available methods that identify active unregulated MM...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb4005468
更新日期：2014-01-17 00:00:00
abstract：:Endothelial progenitor cells (EPCs) and endothelial cells (ECs) play a vital role in endothelialization and vascularization for tissue regeneration. Various EPC/EC targeting biomolecules have been investigated to improve tissue regeneration with limited success often due to their limited functional specificity and str...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.7b00118
更新日期：2017-04-21 00:00:00
abstract：:The publication of the first high-resolution crystal structure of a eukaryotic Cys-loop receptor, GluClα, has provided valuable structural information on this important class of ligand-gated ion channels (LGIC). However, limited functional data exist for the GluCl receptors. Before applying the structural insights fro...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb500323d
更新日期：2014-10-17 00:00:00
abstract：:Photo- or optoacoustics (OA) imaging is increasingly being used as a non-invasive imaging method that can simultaneously reveal structure and function in deep tissue. However, the most frequent transgenic OA labels are current fluorescent proteins that are not optimized for OA imaging. Thus, they lack OA signal streng...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.9b00299
更新日期：2019-09-20 00:00:00
abstract：:The rational design of environmentally sensitive dyes with superior properties is critical for elucidating the fundamental biological processes and understanding the biophysical behavior of cell membranes. In this study, a novel group of fluorene-based push-pull probes was developed for imaging membrane lipids. The de...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.7b00658
更新日期：2017-12-15 00:00:00
abstract：:Phosphoinositides are critical cell-signal mediators present on the plasma membrane. The dynamic change of phosphoinositide concentrations on the membrane including clustering and declustering mediates signal transduction. The importance of phosphoinositides is scored by the fact that they participate in almost all ce...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.6b00067
更新日期：2016-07-15 00:00:00
abstract：:Aminoglycoside antibiotics were among the first antibiotics discovered and used clinically. Although they have never completely fallen out of favor, their importance has waned due to the emergence of other broad-spectrum antibiotics with fewer side effects. Today, with the dramatically increasing rate of infections ca...
journal_title：ACS chemical biology
pub_type： 杂志文章,评审
doi：10.1021/cb3005116
更新日期：2013-01-18 00:00:00
abstract：:Ammonia lyases catalyze the formation of α,β-unsaturated bonds by the elimination of ammonia from their substrates. This conceptually straightforward reaction has been the emphasis of many studies, with the main focus on the catalytic mechanism of these enzymes and/or the use of these enzymes as catalysts for the synt...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb3002792
更新日期：2012-10-19 00:00:00
abstract：:The abundant observation of chemical fragment information for molecular complexities is a major advantage of biological NMR analysis. Thus, the development of a novel technique for NMR signal assignment and metabolite identification may offer new possibilities for exploring molecular complexities. We propose a new sig...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.5b00894
更新日期：2016-04-15 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：:RUVBL1 and RUVBL2 are ATPases associated with diverse cellular activities (AAAs) that form a complex involved in a variety of cellular processes, including chromatin remodeling and regulation of gene expression. RUVBLs have a strong link to oncogenesis, where overexpression is correlated with tumor growth and poor pro...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.8b00904
更新日期：2019-02-15 00:00:00
abstract：:Botulinum neurotoxins (BoNTs) are the most potent toxins known to man and a significant threat as weapons of bioterrorism. BoNTs contain a metalloprotease domain that blocks neurotransmitter release in nerve terminals, resulting in a descending, flaccid paralysis with a 5-10% mortality rate. Existing treatment options...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.8b00937
更新日期：2019-01-18 00:00:00
abstract：:Prenylated indole alkaloid okaramines selectively target insect glutamate-gated chloride channels (GluCls). Because of their highly complex structures, including azocine and azetidine rings, total synthesis of okaramine A or B has not been achieved, preventing evaluation of the biological activities of okaramines. Bio...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.7b00878
更新日期：2018-03-16 00:00:00
abstract：:The limited clinical success of therapeutics targeting cellular signaling processes is due to multiple factors, including off-target effects and complex feedback regulation encoded within the signaling network. To understand these effects, chemical proteomics and chemical genetics tools have been developed to map the ...
journal_title：ACS chemical biology
pub_type： 杂志文章,评审
doi：10.1021/cb1002834
更新日期：2011-01-21 00:00:00
abstract：:Formylglycine (fGly) is a catalytically essential residue found almost exclusively in the active sites of type I sulfatases. Formed by post-translational oxidation of cysteine or serine side chains, this aldehyde-functionalized residue participates in a unique and highly efficient catalytic mechanism for sulfate ester...
journal_title：ACS chemical biology
pub_type： 杂志文章,评审
doi：10.1021/cb500897w
更新日期：2015-01-16 00:00:00
