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Open data
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Basic information
Entry | Database: PDB / ID: 7eg4 | ||||||
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Title | Cryo-EM structure of nauclefine-induced PDE3A-SLFN12 complex | ||||||
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Function / homology | ![]() cGMP-inhibited cyclic-nucleotide phosphodiesterase activity / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | ||||||
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Method | ![]() ![]() ![]() | ||||||
![]() | Liu, N. / Chen, J. / Wang, X.D. / Wang, H.W. | ||||||
![]() | ![]() Title: Structure of PDE3A-SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells. Authors: Jie Chen / Nan Liu / Yinpin Huang / Yuanxun Wang / Yuxing Sun / Qingcui Wu / Dianrong Li / Shuanhu Gao / Hong-Wei Wang / Niu Huang / Xiangbing Qi / Xiaodong Wang / ![]() Abstract: 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 ...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. | ||||||
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 343.8 KB | Display | ![]() |
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PDB format | ![]() | 282.4 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 31105MC ![]() 7eg0C ![]() 7eg1C M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 49552.527 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() References: UniProt: Q14432, ![]() #2: Protein | Mass: 65665.656 Da / Num. of mol.: 2 / Mutation: K213R, S351A, D415S Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() #3: Chemical | #4: Chemical | ChemComp-MG / #5: Chemical | Has ligand of interest | N | |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: ![]() |
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Sample preparation
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Buffer solution | pH: 8 | ||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied![]() ![]() | ||||||||||||||||||||||||
Vitrification![]() | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source![]() ![]() |
Electron lens | Mode: BRIGHT FIELD![]() |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
Software | Name: PHENIX / Version: 1.14_3260: / Classification: refinement |
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CTF correction![]() | Type: PHASE FLIPPING ONLY |
3D reconstruction![]() | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 60683 / Symmetry type: POINT |