7l0i | pdb_00007l0i
Ligand-free YopH G352T
Structural highlights
Publication Abstract from PubMedCatalysis by protein tyrosine phosphatases (PTPs) relies on the motion of a flexible protein loop (the WPD-loop) that carries a residue acting as a general acid/base catalyst during the PTP-catalyzed reaction. The orthogonal substitutions of a noncatalytic residue in the WPD-loops of YopH and PTP1B result in shifted pH-rate profiles from an altered kinetic pK a of the nucleophilic cysteine. Compared to wild type, the G352T YopH variant has a broadened pH-rate profile, similar activity at optimal pH, but significantly higher activity at low pH. Changes in the corresponding PTP1B T177G variant are more modest and in the opposite direction, with a narrowed pH profile and less activity in the most acidic range. Crystal structures of the variants show no structural perturbations but suggest an increased preference for the WPD-loop-closed conformation. Computational analysis confirms a shift in loop conformational equilibrium in favor of the closed conformation, arising from a combination of increased stability of the closed state and destabilization of the loop-open state. Simulations identify the origins of this population shift, revealing differences in the flexibility of the WPD-loop and neighboring regions. Our results demonstrate that changes to the pH dependency of catalysis by PTPs can result from small changes in amino acid composition in their WPD-loops affecting only loop dynamics and conformational equilibrium. The perturbation of kinetic pK a values of catalytic residues by nonchemical processes affords a means for nature to alter an enzyme's pH dependency by a less disruptive path than altering electrostatic networks around catalytic residues themselves. Single Residue on the WPD-Loop Affects the pH Dependency of Catalysis in Protein Tyrosine Phosphatases.,Shen R, Crean RM, Johnson SJ, Kamerlin SCL, Hengge AC JACS Au. 2021 May 24;1(5):646-659. doi: 10.1021/jacsau.1c00054. Epub 2021 Apr 23. PMID:34308419[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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