Abstract：
:Kinase inhibitors are important cancer drugs, but they tend to display limited target specificity, and their target profiles are often challenging to rationalize in terms of molecular mechanism. Here we report that the clinical kinase inhibitor bosutinib recognizes its kinase targets by engaging a pair of conserved structured water molecules in the active site and that many other kinase inhibitors share a similar recognition mechanism. Using the nitrile group of bosutinib as an infrared probe, we show that the gatekeeper residue and one other position in the ATP-binding site control access of the drug to the structured water molecules and that the amino acids found at these positions account for the kinome-wide target spectrum of the drug. Our work highlights the importance of structured water molecules for inhibitor recognition, reveals a new role for the kinase gatekeeper and showcases an effective approach for elucidating the molecular origins of selectivity patterns.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
Levinson NM,Boxer SGdoi
10.1038/nchembio.1404subject
Has Abstractpub_date
2014-02-01 00:00:00pages
127-32issue
2eissn
1552-4450issn
1552-4469pii
nchembio.1404journal_volume
10pub_type
杂志文章abstract：:The resistance of Caenorhabditis elegans to pharmacological perturbation limits its use as a screening tool for novel small bioactive molecules. One strategy to improve the hit rate of small-molecule screens is to preselect molecules that have an increased likelihood of reaching their target in the worm. To learn whic...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.380
更新日期：2010-07-01 00:00:00
abstract：:More than 30 years ago, a calcium-dependent enzyme activity was described that generates N-acyl phosphatidylethanolamines (NAPEs), which are precursors for N-acyl ethanolamine (NAE) lipid transmitters, including the endocannabinoid anandamide. The identity of this calcium-dependent N-acyltransferase (Ca-NAT) has remai...
journal_title：Nature chemical biology
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abstract：: ...
journal_title：Nature chemical biology
pub_type： 评论,杂志文章
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更新日期：2018-06-01 00:00:00
abstract：:RNA G-quadruplex (G4) structures are thought to affect biological processes, including translation and pre-mRNA splicing, but it is not possible at present to demonstrate that they form naturally at specific sequences in long functional RNA molecules. We developed a new strategy, footprinting of long 7-deazaguanine-su...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2228
更新日期：2017-01-01 00:00:00
abstract：:We identify an Arabidopsis pyridoxal-phosphate-dependent aminotransferase, VAS1, whose loss-of-function simultaneously increases amounts of the phytohormone auxin and the ethylene precursor 1-aminocyclopropane-1-carboxylate. VAS1 uses the ethylene biosynthetic intermediate methionine as an amino donor and the auxin bi...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1178
更新日期：2013-04-01 00:00:00
abstract：:Only 25% of bacterial membrane transporters have functional annotation owing to the difficulty of experimental study and of accurate prediction of their function. Here we report a sequence-independent method for high-throughput mining of novel transporters. The method is based on ligand-responsive biosensor systems th...
journal_title：Nature chemical biology
pub_type： 杂志文章
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更新日期：2016-12-01 00:00:00
abstract：:Nature is a diverse and rich source of bioactive pathways or novel building blocks for synthetic biology. In this Perspective, we describe the emerging research field in which metagenomes are functionally interrogated using synthetic biology. This approach substantially expands the set of identified biological activit...
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journal_title：Nature chemical biology
pub_type： 杂志文章
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abstract：:The serotonin6 receptor (5-HT6R) is a promising target for treating cognitive deficits of schizophrenia often linked to alterations of neuronal development. This receptor controls neurodevelopmental processes, but the signaling mechanisms involved remain poorly understood. Using a proteomic strategy, we show that 5-HT...
journal_title：Nature chemical biology
pub_type： 杂志文章
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更新日期：2014-07-01 00:00:00
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pub_type： 杂志文章,评审
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journal_title：Nature chemical biology
pub_type： 杂志文章,评审
doi：10.1038/nchembio.166
更新日期：2009-05-01 00:00:00
abstract：:Proteoglycans are complex glycoconjugates that regulate critical biological pathways in all higher organisms. Bikunin, the simplest proteoglycan, with a single glycosaminoglycan chain, is a serine protease inhibitor used to treat acute pancreatitis. Unlike nucleic acids and proteins, whose synthesis is template driven...
journal_title：Nature chemical biology
pub_type： 杂志文章
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更新日期：2011-10-09 00:00:00
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journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio0308-152
更新日期：2008-03-01 00:00:00
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pub_type： 杂志文章
doi：10.1038/nchembio821
更新日期：2006-11-01 00:00:00
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journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2207
更新日期：2016-12-01 00:00:00
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journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.638
更新日期：2011-08-21 00:00:00
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journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.944
更新日期：2012-04-22 00:00:00
abstract：:The heat shock protein 90 (Hsp90) has a critical role in malignant transformation. Whereas its ability to maintain the functional conformations of mutant and aberrant oncoproteins is established, a transformation-specific regulation of the antiapoptotic phenotype by Hsp90 is poorly understood. By using selective compo...
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pub_type： 杂志文章
doi：10.1038/nchembio.2007.10
更新日期：2007-08-01 00:00:00
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更新日期：2011-10-16 00:00:00
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更新日期：2015-05-01 00:00:00
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journal_title：Nature chemical biology
pub_type： 杂志文章
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更新日期：2017-03-01 00:00:00
abstract：:Bioinorganic chemistry remains a vibrant discipline at the interface of chemistry and the biological sciences. Metal ions function in numerous metalloenzymes, are incorporated into pharmaceuticals and imaging agents, and inspire the synthesis of catalysts used to achieve many chemical transformations. ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio1006-504
更新日期：2006-10-01 00:00:00
abstract：:Mitochondrial electron transport drives ATP synthesis but also generates reactive oxygen species, which are both cellular signals and damaging oxidants. Superoxide production by respiratory complex III is implicated in diverse signaling events and pathologies, but its role remains controversial. Using high-throughput ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1910
更新日期：2015-11-01 00:00:00
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pub_type： 杂志文章
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更新日期：2017-06-01 00:00:00
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journal_title：Nature chemical biology
pub_type： 杂志文章
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更新日期：2006-06-01 00:00:00
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pub_type： 杂志文章
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更新日期：2005-06-01 00:00:00
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journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1823
更新日期：2015-07-01 00:00:00
