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

Chem
Jean B BertoldoGonçalo J L Bernardes

Abstract

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.

Citations

Nov 17, 2020·Frontiers in Chemistry·Dailén G MartínezJean B Bertoldo
May 1, 2021·Chemical Communications : Chem Comm·Yoshifumi HashikawaYasujiro Murata

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Methods Mentioned

BETA
Circular dichroism
X-ray
infrared spectroscopy
nuclear magnetic resonance

Software Mentioned

WaterMap
PDBeFold
PyMOL
FATCAT

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