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 state assuming a 'DFG-in' and an inactive state assuming a 'DFG-out' conformation. Compounds that preferentially bind to the DFG-out conformation are typically called 'type II' inhibitors in contrast to 'type I' inhibitors that bind to the DFG-in conformation. This review surveys the large number of type II inhibitors that have been developed and provides an analysis of their crystallographically determined binding modes. Using a small library of type II inhibitors, we demonstrate that more than 200 kinases can be targeted, suggesting that type II inhibitors may not be intrinsically more selective than type I inhibitors.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Zhao Z,Wu H,Wang L,Liu Y,Knapp S,Liu Q,Gray NSdoi
10.1021/cb500129tsubject
Has Abstractpub_date
2014-06-20 00:00:00pages
1230-41issue
6eissn
1554-8929issn
1554-8937journal_volume
9pub_type
杂志文章,评审abstract：:The epidermal growth-factor-like domain A (EGF-A) of the low-density lipoprotein (LDL) receptor is a promising lead for therapeutic inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9). However, the clinical potential of EGF-A is limited by its suboptimal affinity for PCSK9. Here, we use phage display t...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.0c00991
更新日期：2021-01-29 00:00:00
abstract：:A biophysical understanding of the mechanistic, chemical, and physical origins underlying antibiotic action and resistance is vital to the discovery of novel therapeutics and the development of strategies to combat the growing emergence of antibiotic resistance. The site-specific introduction of stable-isotope labels ...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.9b01054
更新日期：2020-05-15 00:00:00
abstract：:Oligomeric assemblies formed from a variety of disease-associated peptides and proteins have been strongly associated with toxicity in many neurodegenerative conditions, such as Alzheimer's disease. The precise nature of the toxic agents, however, remains still to be established. We show that prefibrillar aggregates o...
journal_title：ACS chemical biology
pub_type： 信件
doi：10.1021/cb1001203
更新日期：2010-08-20 00:00:00
abstract：:Cysteine residues on proteins play key roles in catalysis and regulation. These functional cysteines serve as active sites for nucleophilic and redox catalysis, sites of allosteric regulation, and metal-binding ligands on proteins from diverse classes including proteases, kinases, metabolic enzymes, and transcription ...
journal_title：ACS chemical biology
pub_type： 杂志文章,评审
doi：10.1021/cb3005269
更新日期：2013-02-15 00:00:00
abstract：:The receptor tyrosine kinase EPHA2 (Ephrin type-A receptor 2) plays important roles in oncogenesis, metastasis, and treatment resistance, yet therapeutic targeting, drug discovery, or investigation of EPHA2 biology is hampered by the lack of appropriate inhibitors and structural information. Here, we used chemical pro...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.6b00709
更新日期：2016-12-16 00:00:00
abstract：:To combat the increasing spread of antimicrobial resistance and the shortage of novel anti-infectives, one strategy for the development of new antibiotics is to optimize known chemical scaffolds. Here, we focus on the biosynthetic engineering of Amycolatopsis sulphurea for derivatization of the atypical tetracycline c...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.8b01125
更新日期：2019-03-15 00:00:00
abstract：:Complexity generation in naturally occurring peptide scaffolds can occur either by posttranslational modifications of nascent ribosomal proteins or through post assembly line tailoring of nonribosomal peptides. Short enzymatic pathways utilizing bimodular and trimodular nonribosomal peptide synthetase (NRPS) assembly ...
journal_title：ACS chemical biology
pub_type： 杂志文章,评审
doi：10.1021/cb4001684
更新日期：2013-07-19 00:00:00
abstract：:RAGE (Receptor for Advanced Glycation End-Products) has emerged as a major receptor that mediates vascular inflammation. Signaling through RAGE by damage-associated molecular pattern molecules often leads to uncontrolled inflammation that exacerbates the impact of the underlying disease. Oligomerization of RAGE is bel...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb4001553
更新日期：2013-07-19 00:00:00
abstract：:Glycosaminoglycans (GAGs), such as heparin or heparan sulfate, are required for the in vivo function of chemokines. Chemokines play a crucial role in the recruitment of leukocyte subsets to sites of inflammation and lymphocytes trafficking. GAG-chemokine interactions mediate cell migration and determine which leukocyt...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb700159m
更新日期：2007-11-20 00:00:00
abstract：:Chemical genetics is a powerful approach for identifying therapeutically active small molecules, but identifying the mechanisms of action underlying hit compounds remains challenging. Chemoproteomic platforms have arisen to tackle this challenge and enable rapid mechanistic deconvolution of small-molecule screening hi...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.8b00381
更新日期：2018-08-17 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：:The Morita-Baylis-Hillman reaction forms a carbon-carbon bond between the α-carbon of a conjugated carbonyl compound and a carbon electrophile. The reaction mechanism involves Michael addition of a nucleophile catalyst at the carbonyl β-carbon, followed by bond formation with the electrophile and catalyst disassociati...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb3006227
更新日期：2013-04-19 00:00:00
abstract：:Recent advances in mass spectrometry (MS)-based proteomics allow the identification and quantitation of thousands of posttranslational modification (PTM) sites in a single experiment. This follows from the development of more effective class enrichment strategies, new high performance instrumentation and bioinformatic...
journal_title：ACS chemical biology
pub_type： 杂志文章,评审
doi：10.1021/cb500904b
更新日期：2015-01-16 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：:Hemolysis, a process by which the destruction of red blood cells leads to the release of hemoglobin, is a critical event observed during hemolytic disorders. Under oxidative stress conditions, hemoglobin can release its heme prosthetic group, which is highly cytotoxic and can catalyze the generation of reactive oxygen...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.8b00458
更新日期：2018-08-17 00:00:00
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
更新日期：2013-07-19 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：:N-Acetylneuraminic acid lyase (NAL) is a Class I aldolase that catalyzes the reversible condensation of pyruvate with N-acetyl-d-mannosamine (ManNAc) to yield the sialic acid N-acetylneuraminic acid (Neu5Ac). Aldolases are finding increasing use as biocatalysts for the stereospecific synthesis of complex molecules. In...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb500067z
更新日期：2014-04-18 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：:Protein phosphatases are critical regulators of cellular signaling in both eukaryotes and prokaryotes. The majority of protein phosphatases dephosphorylate phosphoserine/phosphothreonine or phosphotyrosine residues. Recently, however, YwlE, a member of the low-molecular weight protein tyrosine phosphatase (LMW-PTP) fa...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb4001469
更新日期：2013-09-20 00:00:00
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
更新日期：2009-07-17 00:00:00
abstract：:Sublancin 168 is a member of a small group of glycosylated antimicrobial peptides known as glycocins. The solution structure of sublancin 168, a 37-amino-acid peptide produced by Bacillus subtilis 168, has been solved by nuclear magnetic resonance (NMR) spectroscopy. Sublancin comprises two α-helices and a well-define...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb4008106
更新日期：2014-03-21 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：:Ubc13 is an E2 ubiquitin conjugating enzyme that functions in nuclear DNA damage signaling and cytoplasmic NF-κB signaling. Here, we present the structures of complexes of Ubc13 with two inhibitors, NSC697923 and BAY 11-7082, which inhibit DNA damage and NF-κB signaling in human cells. NSC697923 and BAY 11-7082 both i...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.5b00222
更新日期：2015-07-17 00:00:00
abstract：:Microbes are essential to the global ecosystem, but undesirable microbial growth causes issues ranging from food spoilage and infectious diseases to harmful cyanobacterial blooms. The use of chemicals to control microbial growth has achieved significant success, while specific roles for a majority of essential genes i...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.0c00507
更新日期：2020-08-21 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：: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：: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
doi：10.1021/acschembio.7b01013
更新日期：2018-03-16 00:00:00
abstract：:Intracellular reactions on nonenzymatic proteins that activate cellular signals are rarely found. We report one example here that a designed peptide derivative undergoes a nucleophilic reaction specifically with a cytosolic PDZ protein inside cells. This reaction led to the activation of ephrin-B reverse signaling, wh...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.5b00889
更新日期：2016-01-15 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
