Nature Communications (Jul 2021)
Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase
- Colin W. Garvie,
- Xiaoyun Wu,
- Malvina Papanastasiou,
- Sooncheol Lee,
- James Fuller,
- Gavin R. Schnitzler,
- Steven W. Horner,
- Andrew Baker,
- Terry Zhang,
- James P. Mullahoo,
- Lindsay Westlake,
- Stephanie H. Hoyt,
- Marcus Toetzl,
- Matthew J. Ranaghan,
- Luc de Waal,
- Joseph McGaunn,
- Bethany Kaplan,
- Federica Piccioni,
- Xiaoping Yang,
- Martin Lange,
- Adrian Tersteegen,
- Donald Raymond,
- Timothy A. Lewis,
- Steven A. Carr,
- Andrew D. Cherniack,
- Christopher T. Lemke,
- Matthew Meyerson,
- Heidi Greulich
Affiliations
- Colin W. Garvie
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard
- Xiaoyun Wu
- Cancer Program, Broad Institute of MIT and Harvard
- Malvina Papanastasiou
- Proteomics Platform, Broad Institute of MIT and Harvard
- Sooncheol Lee
- Cancer Program, Broad Institute of MIT and Harvard
- James Fuller
- Helix Biostructures
- Gavin R. Schnitzler
- Cancer Program, Broad Institute of MIT and Harvard
- Steven W. Horner
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard
- Andrew Baker
- Cancer Program, Broad Institute of MIT and Harvard
- Terry Zhang
- Thermo Fisher
- James P. Mullahoo
- Proteomics Platform, Broad Institute of MIT and Harvard
- Lindsay Westlake
- Cancer Program, Broad Institute of MIT and Harvard
- Stephanie H. Hoyt
- Cancer Program, Broad Institute of MIT and Harvard
- Marcus Toetzl
- Cancer Program, Broad Institute of MIT and Harvard
- Matthew J. Ranaghan
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard
- Luc de Waal
- Cancer Program, Broad Institute of MIT and Harvard
- Joseph McGaunn
- Cancer Program, Broad Institute of MIT and Harvard
- Bethany Kaplan
- Cancer Program, Broad Institute of MIT and Harvard
- Federica Piccioni
- Genetic Perturbation Platform, Broad Institute of MIT and Harvard
- Xiaoping Yang
- Genetic Perturbation Platform, Broad Institute of MIT and Harvard
- Martin Lange
- Research and Development, Pharmaceuticals, Bayer AG
- Adrian Tersteegen
- Research and Development, Pharmaceuticals, Bayer AG
- Donald Raymond
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard
- Timothy A. Lewis
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard
- Steven A. Carr
- Proteomics Platform, Broad Institute of MIT and Harvard
- Andrew D. Cherniack
- Cancer Program, Broad Institute of MIT and Harvard
- Christopher T. Lemke
- Center for the Development of Therapeutics, Broad Institute of MIT and Harvard
- Matthew Meyerson
- Cancer Program, Broad Institute of MIT and Harvard
- Heidi Greulich
- Cancer Program, Broad Institute of MIT and Harvard
- DOI
- https://doi.org/10.1038/s41467-021-24495-w
- Journal volume & issue
-
Vol. 12,
no. 1
pp. 1 – 16
Abstract
The small molecule DNMDP acts as a velcrin by inducing complex formation between phosphodiesterase PDE3A and SLFN12, which kills cancer cells that express sufficient levels of both proteins. Here, the authors present the cryo-EM structure of the DNMDP-stabilized PDE3A-SLFN12 complex and show that SLFN12 is an RNase. PDE3A binding increases SLFN12 RNase activity, and SLFN12 RNase activity is required for DNMDP-mediated cancer cell killing.
