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- EMDB-31104: Cryo-EM structure of DNMDP-induced PDE3A-SLFN12 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-31104
TitleCryo-EM structure of DNMDP-induced PDE3A-SLFN12 complex
Map data
Sample
  • Complex: dimer of PDE3A-SLFN12 heterodimer
    • Complex: PDE3A
      • Protein or peptide: cGMP-inhibited 3',5'-cyclic phosphodiesterase A
    • Complex: SLFN12
      • Protein or peptide: Schlafen family member 12
  • Ligand: (4~{R})-3-[4-(diethylamino)-3-[oxidanyl(oxidanylidene)-$l^{4}-azanyl]phenyl]-4-methyl-4,5-dihydro-1~{H}-pyridazin-6-one
  • Ligand: MAGNESIUM ION
  • Ligand: ZINC ION
KeywordsPDE3A / SLFN12 / DNMDP / APOPTOSIS
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
cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A / Ribonuclease SLFN12
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsLiu N / Chen J
Funding support1 items
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, 2021-
Header (metadata) releaseNov 3, 2021-
Map releaseNov 3, 2021-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.02
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  • Surface view with fitted model
  • Atomic models: PDB-7eg1
  • Surface level: 0.02
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_31104.png

Downloads & links

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Map

FileDownload / File: emd_31104.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 200 pix.
= 218.2 Å		1.09 Å/pix.
x 200 pix.
= 218.2 Å		1.09 Å/pix.
x 200 pix.
= 218.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.091 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0188 / Movie #1: 0.02
Minimum - Maximum-0.09937186 - 0.16459933
Average (Standard dev.)0.00043365124 (±0.005433381)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 218.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0911.0911.091
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z218.200218.200218.200
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ364364364
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-0.0990.1650.000

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Supplemental data

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Sample components

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Entire : dimer of PDE3A-SLFN12 heterodimer

EntireName: dimer of PDE3A-SLFN12 heterodimer
Components
  • Complex: dimer of PDE3A-SLFN12 heterodimer
    • Complex: PDE3A
      • Protein or peptide: cGMP-inhibited 3',5'-cyclic phosphodiesterase A
    • Complex: SLFN12
      • Protein or peptide: Schlafen family member 12
  • Ligand: (4~{R})-3-[4-(diethylamino)-3-[oxidanyl(oxidanylidene)-$l^{4}-azanyl]phenyl]-4-methyl-4,5-dihydro-1~{H}-pyridazin-6-one
  • Ligand: MAGNESIUM ION
  • Ligand: ZINC ION

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Supramolecule #1: dimer of PDE3A-SLFN12 heterodimer

SupramoleculeName: dimer of PDE3A-SLFN12 heterodimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: PDE3A

SupramoleculeName: PDE3A / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: SLFN12

SupramoleculeName: SLFN12 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2

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Macromolecule #1: cGMP-inhibited 3',5'-cyclic phosphodiesterase A

MacromoleculeName: cGMP-inhibited 3',5'-cyclic phosphodiesterase A / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: 3',5'-cyclic-nucleotide phosphodiesterase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.552527 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: KPILAPEPLV MDNLDSIMEQ LNTWNFPIFD LVENIGRKCG RILSQVSYRL FEDMGLFEAF KIPIREFMNY FHALEIGYRD IPYHNRIHA TDVLHAVWYL TTQPIPGLST VINDHGSTSD SDSDSGFTHG HMGYVFSKTY NVTDDKYGCL SGNIPALELM A LYVAAAMH ...String:
KPILAPEPLV MDNLDSIMEQ LNTWNFPIFD LVENIGRKCG RILSQVSYRL FEDMGLFEAF KIPIREFMNY FHALEIGYRD IPYHNRIHA TDVLHAVWYL TTQPIPGLST VINDHGSTSD SDSDSGFTHG HMGYVFSKTY NVTDDKYGCL SGNIPALELM A LYVAAAMH DYDHPGRTNA FLVATSAPQA VLYNDRSVLE NHHAAAAWNL FMSRPEYNFL INLDHVEFKH FRFLVIEAIL AT DLKKHFD FVAKFNGKVN DDVGIDWTNE NDRLLVCQMC IKLADINGPA KCKELHLQWT DGIVNEFYEQ GDEEASLGLP ISP FMDRSA PQLANLQESF ISHIVGPLCN SYDSAGLMPG KWVEDSDESG DTDDPEEEEE EAPAPNEEET CENNESPKKK TFKR RKIYC QITQHLLQNH KMWKKVIEEE QRLAGIENQ

UniProtKB: cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A

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Macromolecule #2: Schlafen family member 12

MacromoleculeName: Schlafen family member 12 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 65.665656 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: NISVDLETNY AELVLDVGRV TLGENSRKKM KDCKLRKKQN ESVSRAMCAL LNSGGGVIKA EIENEDYSYT KDGIGLDLEN SFSNILLFV PEYLDFMQNG NYFLIFVKSW SLNTSGLRIT TLSSNLYKRD ITSAKVMNAT AALEFLKDMK KTRGRLYLRP E LLAKRPCV ...String:
NISVDLETNY AELVLDVGRV TLGENSRKKM KDCKLRKKQN ESVSRAMCAL LNSGGGVIKA EIENEDYSYT KDGIGLDLEN SFSNILLFV PEYLDFMQNG NYFLIFVKSW SLNTSGLRIT TLSSNLYKRD ITSAKVMNAT AALEFLKDMK KTRGRLYLRP E LLAKRPCV DIQEENNMKA LAGVFFDRTE LDRKEKLTFT ESTHVEIKNF STERLLQRIK EILPQYVSAF ANTDGGYLFI GL NEDKEII GFKAEMSDLD DLEREIEKSI RKMPVHHFCM EKKKINYSCK FLGVYDKGSL CGYVCALRVE RFCCAVFAKE PDS WHVKDN RVMQLTRKEW IQFMVEAEPK FSSAYEEVIS QINTSLPAPH SWPLLEWQRQ RHHCPGLSGR ITYTPENLCR KLFL QHEGL KQLICEEMSS VRKGSLIFSR SWSVDLGLQE NHKVLCDALL ISQDSPPVLY TFHMVQDEEF KGYSTQTALT LKQKL AKIG GYTKKVCVMT KIFYLSPEGM TSCQYDLRSQ VIYPESYYFT RRKYLLKALF KALKRLKSLR DQFSFAENLY QIIGID CFQ KNDK

UniProtKB: Ribonuclease SLFN12

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Macromolecule #3: (4~{R})-3-[4-(diethylamino)-3-[oxidanyl(oxidanylidene)-$l^{4}-aza...

MacromoleculeName: (4~{R})-3-[4-(diethylamino)-3-[oxidanyl(oxidanylidene)-$l^{4}-azanyl]phenyl]-4-methyl-4,5-dihydro-1~{H}-pyridazin-6-one
type: ligand / ID: 3 / Number of copies: 2 / Formula: X5M
Molecular weightTheoretical: 305.352 Da
Chemical component information

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

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 4 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 5 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 203914
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: MAXIMUM LIKELIHOOD

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