Abstract：
:Ubiquitin specific protease 7 (USP7) regulates the protein stability of key cellular regulators in pathways ranging from apoptosis to neuronal development, making it a promising therapeutic target. Here we used an engineered, activated variant of the USP7 catalytic domain to perform structure-activity studies of electrophilic peptidomimetic inhibitors. Employing this USP7 variant, we found that inhibitors with a cyanopyrrolidine warhead unexpectedly promoted a β-elimination reaction of the initial covalent adducts, thereby converting the active-site cysteine residue to dehydroalanine. We determined that this phenomenon is specific for the USP7 catalytic cysteine and that structural features of the inhibitor and protein microenvironment impact elimination rates. Using comprehensive docking studies, we propose that the characteristic conformational dynamics of USP7 allow access to conformations that promote the ligand-induced elimination. Unlike in conventional reversible-covalent inhibition, the compounds described here irreversibly destroy a catalytic residue while simultaneously converting the inhibitor to a nonelectrophilic byproduct. Accordingly, this unexpected finding expands the scope of covalent inhibitor modalities and offers intriguing insights into enzyme-inhibitor dynamics.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Bashore C,Jaishankar P,Skelton NJ,Fuhrmann J,Hearn BR,Liu PS,Renslo AR,Dueber ECdoi
10.1021/acschembio.0c00031subject
Has Abstractpub_date
2020-06-19 00:00:00pages
1392-1400issue
6eissn
1554-8929issn
1554-8937journal_volume
15pub_type
杂志文章abstract：:Understanding the interactions between small interfering RNAs (siRNAs) and the RNA-induced silencing complex (RISC), the key protein complex of RNA interference (RNAi), is of great importance to the development of siRNAs with improved biological and potentially therapeutic function. Although various chemically modifie...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb300174c
更新日期：2012-08-17 00:00:00
abstract：:Methicillin resistance in Staphylococcus aureus depends on the production of mecA, which encodes penicillin-binding protein 2A (PBP2A), an acquired peptidoglycan transpeptidase (TP) with reduced susceptibility to β-lactam antibiotics. PBP2A cross-links nascent peptidoglycan when the native TPs are inhibited by β-lacta...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb100269f
更新日期：2011-01-21 00:00:00
abstract：:Reporter gene assays (RGAs) are commonly used to measure biological pathway modulation by small molecules. Understanding how such compounds interact with the reporter enzyme is critical to accurately interpret RGA results. To improve our understanding of reporter enzymes and to develop optimal RGA systems, we investig...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb3007264
更新日期：2013-05-17 00:00:00
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
更新日期：2019-05-17 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：: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：:New methodologies for site-specifically radiolabeling proteins with (18)F are required to generate high quality radiotracers for preclinical and clinical applications with positron emission tomography. Herein, we report an approach by which we use lipoic acid ligase (LplA) to conjugate [(18)F]-fluorooctanoic acid to a...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.6b00172
更新日期：2016-06-17 00:00:00
abstract：:Establishing the relative configuration of a bioactive natural product represents the most challenging part in determining its structure. Residual dipolar couplings (RDCs) are sensitive probes of the relative spatial orientation of internuclear vectors. We adapted a force field structure calculation methodology to all...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.7b00281
更新日期：2017-08-18 00:00:00
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
doi：10.1021/cb100179t
更新日期：2010-07-16 00:00:00
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
doi：10.1021/acschembio.0c00145
更新日期：2020-06-19 00:00:00
abstract：:The innate immune system provides the first line of defense against pathogens through the recognition of nonspecific patterns in RNA to protect the cell in a generalized way. The human RNA-activated protein kinase, PKR, is a dsRNA binding protein and an essential sensor in the innate immune response, which recognizes ...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.6b00081
更新日期：2016-04-15 00:00:00
abstract：:Detection of metabolites and post-translational modifications can be achieved using the azide as a bioorthogonal chemical reporter. Once introduced into target biomolecules, either metabolically or through chemical modification, the azide can be tagged with probes using one of three highly selective reactions: the Sta...
journal_title：ACS chemical biology
pub_type： 信件
doi：10.1021/cb6003228
更新日期：2006-11-21 00:00:00
abstract：:Mutations that constitutively activate the phosphatidyl-inositol-3-kinase (PI3K) signaling pathway, including alterations in PI3K, PTEN, and AKT, are found in a variety of human cancers, implicating the PI3K lipid kinase as an attractive target for the development of therapeutic agents to treat cancer and other relate...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb800039y
更新日期：2008-05-16 00:00:00
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
更新日期：2006-05-23 00:00:00
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
doi：10.1021/acschembio.9b00270
更新日期：2019-06-21 00:00:00
abstract：:HIV infection is pandemic in humans and is responsible for millions of deaths every year. The discovery of new cellular targets that can be used to prevent the infection process represents a new opportunity for developing more effective antiviral drugs. In this context, dendritic cell-specific ICAM-3 grabbing non-inte...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb900216e
更新日期：2010-03-19 00:00:00
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
doi：10.1021/cb5004527
更新日期：2015-01-16 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：: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：:Enzymatic transfer of the AMP portion of ATP to substrate proteins has recently been described as an essential mechanism of bacterial infection for several pathogens. The first AMPylator to be discovered, VopS from Vibrio parahemolyticus, catalyzes the transfer of AMP onto the host GTPases Cdc42 and Rac1. Modification...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb4006886
更新日期：2014-02-21 00:00:00
abstract：:This report highlights the advantages of low-affinity, multivalent interactions to recognize one cell type over another. Our goal was to devise a strategy to mediate selective killing of tumor cells, which are often distinguished from normal cells by their higher levels of particular cell surface receptors. To test wh...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb6003788
更新日期：2007-02-20 00:00:00
abstract：:The emergence of multidrug-resistant Staphylococcus aureus strains has become a serious clinical problem. Iron is absolutely required for the bacterial growth, virulence associated with colonization, and survival from the host immune system. The FeoB protein is a major iron permease in bacterial ferrous iron transport...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.0c00842
更新日期：2021-01-15 00:00:00
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
更新日期：2015-07-17 00:00:00
abstract：:O-linked N-acetylglucosamine ( O-GlcNAc) is a ubiquitous post-translational modification of proteins and is essential for cell function. Quantifying the dynamics of O-GlcNAcylation in a proteome-wide level is critical for uncovering cellular mechanisms and functional roles of O-GlcNAcylation in cells. Here, we develop...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.8b01052
更新日期：2019-01-18 00:00:00
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
更新日期：2016-03-18 00:00:00
abstract：:We report progress toward a general strategy for mimicking the recognition properties of specific α-helices within natural proteins through the use of oligomers that are less susceptible than conventional peptides to proteolysis. The oligomers contain both α- and β-amino acid residues, with the density of the β subuni...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.5b00109
更新日期：2015-07-17 00:00:00
abstract：:Fe(III) delivery from blood plasma to cells via the transferrin (Tf) cycle was studied intensively due to its crucial role in Fe homeostasis. Tf-cycle disruptions are linked to anemia, infections, immunodeficiency, and neurodegeneration. Biolayer interferometry (BLI) enabled direct kinetic and thermodynamic measuremen...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.8b01100
更新日期：2019-05-17 00:00:00
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
doi：10.1021/cb300130k
更新日期：2012-09-21 00:00:00
abstract：:Toxic heavy metals have been considered to be harmful environmental contaminations. The molecular mechanisms of heavy-metals-induced cytotoxicity and carcinogenicity are still not well elucidated. Previous reports showed exposures to toxic heavy metals can cause a change of DNA cytosine methylation (5-methylcytosine, ...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.7b00170
更新日期：2017-06-16 00:00:00
abstract：:The ubiquitin proteasome system is widely postulated to be a new and important field of drug discovery for the future, with the ubiquitin specific proteases (USPs) representing one of the more attractive target classes within the area. Many USPs have been linked to critical axes for therapeutic intervention, and the f...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.7b00334
更新日期：2017-12-15 00:00:00
