Nature Communications (Jun 2022)
Allosteric inhibition of PPM1D serine/threonine phosphatase via an altered conformational state
- Peter G. Miller,
- Murugappan Sathappa,
- Jamie A. Moroco,
- Wei Jiang,
- Yue Qian,
- Sumaiya Iqbal,
- Qi Guo,
- Andrew O. Giacomelli,
- Subrata Shaw,
- Camille Vernier,
- Besnik Bajrami,
- Xiaoping Yang,
- Cerise Raffier,
- Adam S. Sperling,
- Christopher J. Gibson,
- Josephine Kahn,
- Cyrus Jin,
- Matthew Ranaghan,
- Alisha Caliman,
- Merissa Brousseau,
- Eric S. Fischer,
- Robert Lintner,
- Federica Piccioni,
- Arthur J. Campbell,
- David E. Root,
- Colin W. Garvie,
- Benjamin L. Ebert
Affiliations
- Peter G. Miller
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School
- Murugappan Sathappa
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard University
- Jamie A. Moroco
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard University
- Wei Jiang
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard University
- Yue Qian
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard University
- Sumaiya Iqbal
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard University
- Qi Guo
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard University
- Andrew O. Giacomelli
- Broad Institute of MIT and Harvard University
- Subrata Shaw
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard University
- Camille Vernier
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard University
- Besnik Bajrami
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard University
- Xiaoping Yang
- Broad Institute of MIT and Harvard University
- Cerise Raffier
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard University
- Adam S. Sperling
- Broad Institute of MIT and Harvard University
- Christopher J. Gibson
- Broad Institute of MIT and Harvard University
- Josephine Kahn
- Department of Internal Medicine, Brigham and Women’s Hospital, Harvard Medical School
- Cyrus Jin
- Department of Cancer Biology, Dana-Farber Cancer Institute
- Matthew Ranaghan
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard University
- Alisha Caliman
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard University
- Merissa Brousseau
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard University
- Eric S. Fischer
- Department of Cancer Biology, Dana-Farber Cancer Institute
- Robert Lintner
- Broad Institute of MIT and Harvard University
- Federica Piccioni
- Broad Institute of MIT and Harvard University
- Arthur J. Campbell
- Broad Institute of MIT and Harvard University
- David E. Root
- Broad Institute of MIT and Harvard University
- Colin W. Garvie
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard University
- Benjamin L. Ebert
- Broad Institute of MIT and Harvard University
- DOI
- https://doi.org/10.1038/s41467-022-30463-9
- Journal volume & issue
-
Vol. 13,
no. 1
pp. 1 – 16
Abstract
In this work, the authors report a sophisticated combination of genetic, biophysical, and biochemical analyses to identifies the cycling conformational states of PPM1D. The findings reveal how an allosteric inhibitor locks the protein into a conformationally inactive state, and explain the distribution of PPM1D activating mutations in cancer.
