Abstract：
:Kinetic parameters of protein-ligand interactions are progressively acknowledged as valuable information for rational drug discovery. However, a targeted optimization of binding kinetics is not easy to achieve, and further systematic studies are necessary to increase the understanding about molecular mechanisms involved. We determined association and dissociation rate constants for 17 inhibitors of the metalloprotease thermolysin by surface plasmon resonance spectroscopy and correlated kinetic data with high-resolution crystal structures in complex with the protein. From the structure-kinetics relationship, we conclude that the strength of interaction with Asn112 correlates with the rate-limiting step of dissociation. This residue is located at the beginning of a β-strand motif that lines the binding cleft and is commonly believed to align a substrate for catalysis. A reduced mobility of the Asn112 side chain owing to an enhanced engagement in charge-assisted hydrogen bonds prevents the conformational adjustment associated with ligand release and transformation of the enzyme to its open state. This hypothesis is supported by kinetic data of ZFPLA, a known pseudopeptidic inhibitor of thermolysin, which blocks the conformational transition of Asn112. Interference with this retrograde induced-fit mechanism results in variation of the residence time of thermolysin inhibitors by a factor of 74 000. The high conservation of this structural motif within the M4 and M13 metalloprotease families underpins the importance of this feature and has significant implications for drug discovery.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Cramer J,Krimmer SG,Fridh V,Wulsdorf T,Karlsson R,Heine A,Klebe Gdoi
10.1021/acschembio.6b00979subject
Has Abstractpub_date
2017-01-20 00:00:00pages
225-233issue
1eissn
1554-8929issn
1554-8937journal_volume
12pub_type
杂志文章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：: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：:Bioorthogonal ligation methods that allow the selective conjugation of fluorophores or biotin to proteins and small molecule probes that contain inert chemical handles are an important component of many chemical proteomic strategies. Here, we present a new catch-and-release enrichment strategy that utilizes a hexylchl...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb300623a
更新日期：2013-04-19 00:00:00
abstract：:This Letter reports a family of novel antimicrobial compounds obtained by combining peptide library screening with structure-based design. Library screening led to the identification of a human LL-37 peptide resistant to chymotrypsin. This d-amino-acid-containing peptide template was active against Escherichia coli bu...
journal_title：ACS chemical biology
pub_type： 信件
doi：10.1021/cb500475y
更新日期：2014-09-19 00:00:00
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：:Desferrioxamine B (DFOB) was discovered in the late 1950s as a hydroxamic acid metabolite of the soil bacterium Streptomyces pilosus. The exquisite affinity of DFOB for Fe(III) identified its potential for removing excess iron from patients with transfusion-dependent hemoglobin disorders. Many studies have used semisy...
journal_title：ACS chemical biology
pub_type： 杂志文章,评审
doi：10.1021/acschembio.7b00851
更新日期：2018-01-19 00:00:00
abstract：:Fusicoccin A is a diterpene glucoside phytotoxin generated by the fungal pathogen Phomopsis amygdali that causes the plant disease constriction canker, first discovered in New Jersey peach orchards in the 1930s. Fusicoccin A is also an emerging new lead in cancer chemotherapy. The hydrocarbon precursor of fusicoccin A...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.5b00960
更新日期：2016-04-15 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：:The canonical NF-κB signaling pathway is a mediator of the cellular inflammatory response and a target for developing therapeutics for multiple human diseases. The furthest downstream proteins in the pathway, the p50/p65 transcription factor heterodimer, have been recalcitrant toward small molecule inhibition despite ...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.6b00751
更新日期：2017-01-20 00:00:00
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journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.7b00470
更新日期：2017-09-15 00:00:00
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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 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
doi：10.1021/cb200388k
更新日期：2012-03-16 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：:Despite being extensively characterized structurally and biochemically, the functional role of histone deacetylase 8 (HDAC8) has remained largely obscure due in part to a lack of known cellular substrates. Herein, we describe an unbiased approach using chemical tools in conjunction with sophisticated proteomics method...
journal_title：ACS chemical biology
pub_type： 信件
doi：10.1021/cb500492r
更新日期：2014-10-17 00:00:00
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 s...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.7b00154
更新日期：2017-06-16 00:00:00
abstract：:Extracellular expression of heat shock protein 90 (eHsp90) by tumor cells is correlated with malignancy. Development of small molecule probes that can detect eHsp90 in vivo may therefore have utility in the early detection of malignancy. We synthesized a cell impermeable far-red fluorophore-tagged Hsp90 inhibitor to t...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.7b00006
更新日期：2017-04-21 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：: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：:Hydrogen sulfide (H2S) is an endogenously produced gas that is toxic at high concentrations. It is eliminated by a dedicated mitochondrial sulfide oxidation pathway, which connects to the electron transfer chain at the level of complex III. Direct reduction of cytochrome c (Cyt C) by H2S has been reported previously b...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.8b00463
更新日期：2018-08-17 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：: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
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更新日期：2007-09-21 00:00:00
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pub_type： 杂志文章,评审
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更新日期：2007-07-20 00:00:00
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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
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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
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journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb200176v
更新日期：2011-09-16 00:00:00
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
doi：10.1021/acschembio.6b01053
更新日期：2017-02-17 00:00:00
abstract：:WS9326A and annimycin are produced by Streptomyces asterosporus DSM 41452. WS9326A is a nonribosomal peptide synthetase-(NRPS-) derived depsipeptide containing a cinnamoyl moiety, while annimycin is a linear polyketide bearing a 2-amino-3-hydroxycyclopent-2-enone (C5N) group. Both gene clusters have been sequenced and...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.9b00351
更新日期：2019-08-16 00:00:00
abstract：:The quest for ever more selective kinase inhibitors as potential future drugs has yielded a large repertoire of chemical probes that are selective for specific kinase conformations. These probes have been useful tools to obtain structural snapshots of kinase conformational plasticity. Similarly, kinetic and thermodyna...
journal_title：ACS chemical biology
pub_type： 杂志文章,评审
doi：10.1021/cb500870a
更新日期：2015-01-16 00:00:00
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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：: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
