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TitleStructure of PDE3A-SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 6204, Year 2021
Publish dateOct 27, 2021
AuthorsJie Chen / Nan Liu / Yinpin Huang / Yuanxun Wang / Yuxing Sun / Qingcui Wu / Dianrong Li / Shuanhu Gao / Hong-Wei Wang / Niu Huang / Xiangbing Qi / Xiaodong Wang /
PubMed AbstractMolecular glues are a class of small molecular drugs that mediate protein-protein interactions, that induce either the degradation or stabilization of target protein. A structurally diverse group of ...Molecular glues are a class of small molecular drugs that mediate protein-protein interactions, that induce either the degradation or stabilization of target protein. A structurally diverse group of chemicals, including 17-β-estradiol (E2), anagrelide, nauclefine, and DNMDP, induces apoptosis by forming complexes with phosphodiesterase 3A (PDE3A) and Schlafen 12 protein (SLFN12). They do so by binding to the PDE3A enzymatic pocket that allows the compound-bound PDE3A to recruit and stabilize SLFN12, which in turn blocks protein translation, leading to apoptosis. In this work, we report the high-resolution cryo-electron microscopy structure of PDE3A-SLFN12 complexes isolated from cultured HeLa cells pre-treated with either anagrelide, or nauclefine, or DNMDP. The PDE3A-SLFN12 complexes exhibit a butterfly-like shape, forming a heterotetramer with these small molecules, which are packed in a shallow pocket in the catalytic domain of PDE3A. The resulting small molecule-modified interface binds to the short helix (E552-I558) of SLFN12 through hydrophobic interactions, thus "gluing" the two proteins together. Based on the complex structure, we designed and synthesized analogs of anagrelide, a known drug used for the treatment of thrombocytosis, to enhance their interactions with SLFN12, and achieved superior efficacy in inducing apoptosis in cultured cells as well as in tumor xenografts.
External linksNat Commun / PubMed:34707099 / PubMed Central
MethodsEM (single particle)
Resolution3.2 - 3.4 Å
Structure data

31103

7eg0

EMDB-31103, PDB-7eg0:
Cryo-EM structure of anagrelide-induced PDE3A-SLFN12 complex
Method: EM (single particle) / Resolution: 3.4 Å

31104

7eg1

EMDB-31104, PDB-7eg1:
Cryo-EM structure of DNMDP-induced PDE3A-SLFN12 complex
Method: EM (single particle) / Resolution: 3.2 Å

31105

7eg4

EMDB-31105, PDB-7eg4:
Cryo-EM structure of nauclefine-induced PDE3A-SLFN12 complex
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-J33:
6,7-bis(chloranyl)-3,5-dihydro-1H-imidazo[2,1-b]quinazolin-2-one / Anagrelide

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-X5M:
(4~{R})-3-[4-(diethylamino)-3-[oxidanyl(oxidanylidene)-$l^{4}-azanyl]phenyl]-4-methyl-4,5-dihydro-1~{H}-pyridazin-6-one

ChemComp-J36:
Parvine

Source
  • homo sapiens (human)
KeywordsAPOPTOSIS / anagrelide / PDE3A / SLFN12 / DNMDP / nauclefine

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