Evidence map›Paper›PMID 34272366›Full record

ArticleNature communications2021

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 and 18 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.

0numbers the graph read from it
0cells of the map it votes in
61citing papers in PubMed
5.0field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

61 citing papers in PubMed, 86 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
  4. Article
  5. Article
  6. Pan-cancer ex vivo target evaluation of phosphodiesterase 3 A (PDE3A).Journal of molecular medicine (Berlin, Germany) · 2026
    Article
  7. Article
  8. Article
  9. Article
  10. Article
  11. Review
  12. Review
  13. Review
  14. Article
  15. Pharmacokinetic profile andDrug delivery · 2025
    Article
  16. Review
  17. Article
  18. Phosphodiesterase 3 A expression in gastrointestinal stromal tumors.Virchows Archiv : an international journal of pathology · 2025
    Article
  19. Human Schlafen 14 Cleavage of Short Double-Stranded RNAs Underpins its Antiviral Activity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025
    Article
  20. Article

1 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

28 authors at 5 institutions in 2 countries.

Colin W Garvie *Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Xiaoyun Wu *Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Malvina PapanastasiouProteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0003-3378-6612
Sooncheol LeeCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
James FullerHelix Biostructures, Indianapolis, IN, USA.
Gavin R SchnitzlerCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Steven W HornerCenter for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0002-4028-3071
Andrew BakerCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Terry ZhangThermo Fisher, San Jose, CA, USA.
James P MullahooProteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0002-5469-4066
Lindsay WestlakeCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stephanie H HoytCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0003-2570-6838
Marcus ToetzlCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Matthew J RanaghanCenter for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0003-3572-5127
Luc de WaalCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Joseph McGaunnCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0002-7754-8029
Bethany KaplanCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Federica PiccioniGenetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Xiaoping YangGenetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Martin LangeResearch and Development, Pharmaceuticals, Bayer AG, Berlin, Germany.
Adrian TersteegenResearch and Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany.
Donald RaymondCenter for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Timothy A LewisCenter for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Steven A CarrProteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0002-7203-4299
Andrew D CherniackCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0003-0470-0111
Christopher T LemkeCenter for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Matthew MeyersonCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0002-9133-8108
Heidi GreulichCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. heidig@broadinstitute.org.ORCID 0000-0001-5571-9862
Broad Institute · USBayer (Germany) · DEHelix Biomedix (United States) · USNuvisan (Germany) · DEThermo Fisher Scientific (United States) · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

DNMDP and related compounds, or velcrins, induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express elevated levels of both proteins. The mechanisms by which velcrins induce complex formation, and how the PDE3A-SLFN12 complex causes cancer cell death, are not fully understood. Here, we show that PDE3A and SLFN12 form a heterotetramer stabilized by binding of DNMDP. Interactions between the C-terminal alpha helix of SLFN12 and residues near the active site of PDE3A are required for complex formation, and are further stabilized by interactions between SLFN12 and DNMDP. Moreover, we demonstrate that SLFN12 is an RNase, that PDE3A binding increases SLFN12 RNase activity, and that SLFN12 RNase activity is required for DNMDP response. This new mechanistic understanding will facilitate development of velcrin compounds into new cancer therapies.

Indexed as

Adenosine MonophosphateCalorimetry, Differential ScanningCatalytic DomainCell SurvivalCryoelectron MicroscopyCyclic Nucleotide Phosphodiesterases, Type 3EndoribonucleasesHEK293 CellsHeLa CellsHumansIntracellular Signaling Peptides and ProteinsKineticsMass SpectrometryMultienzyme ComplexesMutationProtein Binding6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-oneAdenosine MonophosphateCyclic Nucleotide Phosphodiesterases, Type 3EndoribonucleasesIntracellular Signaling Peptides and ProteinsMultienzyme ComplexesPDE3A protein, humanPyridazinesRecombinant ProteinsSLFN12 protein, humanTetrahydroisoquinolinestrequinsin

Identifiers

PMID34272366
PMCPMC8285493
OpenAlexW3181471647

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.