PPM1B utilizes a trinuclear metal architecture for phosphatase activity
Stevens, R. P.; Solodushko, V.; Wierzbicki, A.; Rich, T. C.; Alexeyev, M. F.; Thompson, M. K.; Stone, M.; Hall, C.; deWeever, A.; Sayner, S. L.; Stevens, T.; Andrews, J.; Prakash, A.; Honkanen, R. E.; Lee, J. Y.; Salter, E. A.; Swingle, M. R.
Show abstract
The metal-dependent protein phosphatase (PPM/PP2C) family regulates innate immune and cell death pathways through reversible phosphorylation. Although these enzymes contain a conserved third Mg2+/Mn2+ ion (M3) that is essential for activity, its chemical role in phosphate hydrolysis has remained unclear. Here, we report studies that reveal PPM1B promotes cell death during Pseudomonas aeruginosa infection and utilizes a trinuclear metal center in which M3 directly coordinates the substrate phosphate, positioning it for in-line SN2 hydrolysis. In addition to substrate orientation, M3 positions a water molecule to protonate the departing alkoxide, stabilizing the leaving-group. Functionally, M3 substitutes for the arginine clamp in phosphoprotein phosphatases (PPP), revealing that these evolutionarily distinct phosphatase families have converged on the same chemical strategy through fundamentally different catalytic architectures. Together, these findings define a three-metal mechanism in PPM phosphatases and identify the M3 site as a rare and potentially druggable feature for immune and infectious diseases.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Structural elucidation of the heterodimeric cis-prenyltransferase NgBR/DHDDS complex reveals novel insights in regulation of protein glycosylation 95%
- Structural basis of the catalytic and allosteric mechanism of bacterial acetyltransferase PatZ 95%
- Nucleotide and metalloid-driven conformational changes in the arsenite efflux ATPase ArsA 95%
Similar papers in this journal
Similar papers in this journal
- Molecular mechanism of Mad2 conformational conversion promoted by the Mad2-interaction motif of Cdc20 95%
- Genetic encoding of 3-nitro-tyrosine reveals the impacts of 14-3-3 nitration on client binding and dephosphorylation 95%
- Structures of plasmepsin X from P. falciparum reveal a novel inactivation mechanism of the zymogen and molecular basis for binding of inhibitors in mature enzyme 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.