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- PDB-7eg1: Cryo-EM structure of DNMDP-induced PDE3A-SLFN12 complex -

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Basic information

Entry
Database: PDB / ID: 7eg1
TitleCryo-EM structure of DNMDP-induced PDE3A-SLFN12 complex
Components
  • Schlafen family member 12
  • cGMP-inhibited 3',5'-cyclic phosphodiesterase A
KeywordsAPOPTOSIS / PDE3A / SLFN12 / DNMDP
Function / homology
Function and homology information


3',5'-cGMP-inhibited cyclic-nucleotide phosphodiesterase activity / estrogen binding / regulation of ribonuclease activity / positive regulation of oocyte development / regulation of meiotic nuclear division / cellular response to cGMP / rRNA catabolic process / negative regulation of cAMP-mediated signaling / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of vascular permeability ...3',5'-cGMP-inhibited cyclic-nucleotide phosphodiesterase activity / estrogen binding / regulation of ribonuclease activity / positive regulation of oocyte development / regulation of meiotic nuclear division / cellular response to cGMP / rRNA catabolic process / negative regulation of cAMP-mediated signaling / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of vascular permeability / negative regulation of vascular permeability / oocyte maturation / 3',5'-cyclic-nucleotide phosphodiesterase / cGMP-mediated signaling / nuclear estrogen receptor activity / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / RNA nuclease activity / cellular response to transforming growth factor beta stimulus / cAMP-mediated signaling / apoptotic signaling pathway / lipid metabolic process / ribosome binding / G alpha (s) signalling events / Hydrolases; Acting on ester bonds / response to xenobiotic stimulus / G protein-coupled receptor signaling pathway / negative regulation of apoptotic process / membrane / nucleus / metal ion binding / cytosol
Similarity search - Function
: / Schlafen, GTPase-like domain / Schlafen family / Orthopoxvirus B3 protein / Poxviridae B3 protein / Schlafen, AlbA_2 domain / Schlafen, AlbA_2 domain superfamily / Schlafen, AlbA_2 / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site ...: / Schlafen, GTPase-like domain / Schlafen family / Orthopoxvirus B3 protein / Poxviridae B3 protein / Schlafen, AlbA_2 domain / Schlafen, AlbA_2 domain superfamily / Schlafen, AlbA_2 / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase domain signature. / 3'5'-cyclic nucleotide phosphodiesterase domain profile. / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain
Similarity search - Domain/homology
Chem-X5M / cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A / Ribonuclease SLFN12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsLiu, N. / Chen, J. / Wang, X.D. / Wang, H.W.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2021
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.
History
DepositionMar 23, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 3, 2021Provider: repository / Type: Initial release
Revision 1.1May 25, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 6, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: cGMP-inhibited 3',5'-cyclic phosphodiesterase A
B: Schlafen family member 12
C: cGMP-inhibited 3',5'-cyclic phosphodiesterase A
D: Schlafen family member 12
hetero molecules


Theoretical massNumber of molelcules
Total (without water)231,27512
Polymers230,4364
Non-polymers8398
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area14450 Å2
ΔGint-109 kcal/mol
Surface area80960 Å2

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Components

#1: Protein cGMP-inhibited 3',5'-cyclic phosphodiesterase A / Cyclic GMP-inhibited phosphodiesterase A / CGI-PDE A


Mass: 49552.527 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE3A / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
References: UniProt: Q14432, 3',5'-cyclic-nucleotide phosphodiesterase
#2: Protein Schlafen family member 12


Mass: 65665.656 Da / Num. of mol.: 2 / Mutation: K213R, S351A, D415S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLFN12 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q8IYM2
#3: Chemical ChemComp-X5M / (4~{R})-3-[4-(diethylamino)-3-[oxidanyl(oxidanylidene)-$l^{4}-azanyl]phenyl]-4-methyl-4,5-dihydro-1~{H}-pyridazin-6-one


Mass: 305.352 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H21N4O3
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1dimer of PDE3A-SLFN12 heterodimerCOMPLEX#1-#20RECOMBINANT
2PDE3ACOMPLEX#11RECOMBINANT
3SLFN12COMPLEX#21RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
21Homo sapiens (human)9606HEK293
32Homo sapiens (human)9606HEK293
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.14_3260: / Classification: refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 203914 / Symmetry type: POINT

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