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A Water-Bridged Cysteine-Cysteine Redox Regulation Mechanism in Bacterial Protein Tyrosine Phosphatases

Bertoldo, JB and Rodrigues, T and Dunsmore, L and Aprile, FA and Marques, MC and Rosado, LA and Boutureira, O and Steinbrecher, TB and Sherman, W and Corzana, F and Terenzi, H and Bernardes, GJL (2017) A Water-Bridged Cysteine-Cysteine Redox Regulation Mechanism in Bacterial Protein Tyrosine Phosphatases. Chem, 3. pp. 665-677. ISSN 2451-9294

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The emergence of multidrug-resistant Mycobacterium tuberculosis (Mtb) strains highlights the need to develop more efficacious and potent drugs. However, this goal is dependent on a comprehensive understanding of Mtb virulence protein effectors at the molecular level. Here, we used a post-expression cysteine (Cys)-to-dehydrolanine (Dha) chemical editing strategy to identify a water-mediated motif that modulates accessibility of the protein tyrosine phosphatase A (PtpA) catalytic pocket. Importantly, this water-mediated Cys-Cys non-covalent motif is also present in the phosphatase SptpA from Staphylococcus aureus, which suggests a potentially preserved structural feature among bacterial tyrosine phosphatases. The identification of this structural water provides insight into the known resistance of Mtb PtpA to the oxidative conditions that prevail within an infected host macrophage. This strategy could be applied to extend the understanding of the dynamics and function(s) of proteins in their native state and ultimately aid in the design of small-molecule modulators.

Item Type: Article
Uncontrolled Keywords: mycobacterium tuberculosis SDG3: Good health and well-being biophysics chemical biology chemical mutagenesis computational chemistry enzymology protein tyrosine phosphatase water bridge
Depositing User: Cron Job
Date Deposited: 25 Jun 2019 02:49
Last Modified: 13 Apr 2021 09:35
DOI: 10.1016/j.chempr.2017.07.009