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    Reactivities of the Front Pocket N-Terminal Cap Cysteines in Human Kinases.

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    Author
    Liu, Ruibin
    Zhan, Shaoqi
    Che, Ye
    Shen, Jana
    Date
    2021-10-14
    Journal
    Journal of Medicinal Chemistry
    Publisher
    American Chemical Society
    Type
    Article
    
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    See at
    https://doi.org/10.1021/acs.jmedchem.1c01186
    http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8812259/
    Abstract
    The front pocket (FP) N-terminal cap (Ncap) cysteine is the most popular site of covalent modification in kinases. A long-standing hypothesis associates the Ncap position with cysteine hyper-reactivity; however, traditional computational predictions suggest that the FP Ncap cysteines are predominantly unreactive. Here we applied the state-of-the-art continuous constant pH molecular dynamics (CpHMD) to test the Ncap hypothesis. Simulations found that the Ncap cysteines of BTK/BMX/TEC/ITK/TXK, JAK3, and MKK7 are reactive to varying degrees; however, those of BLK and EGFR/ERBB2/ERBB4 possessing a Ncap+3 aspartate are unreactive. Analysis suggested that hydrogen bonding and electrostatic interactions drive the reactivity, and their absence renders the Ncap cysteine unreactive. To further test the Ncap hypothesis, we examined the FP Ncap+2 cysteines in JNK1/JNK2/JNK3 and CASK. Our work offers a systematic understanding of the cysteine structure-reactivity relationship and illustrates the use of CpHMD to differentiate cysteines toward the design of targeted covalent inhibitors with reduced chemical reactivities.
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17878
    ae974a485f413a2113503eed53cd6c53
    10.1021/acs.jmedchem.1c01186
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