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- PDB-7l28: Crystal structure of the catalytic domain of human PDE3A bound to... -
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Basic information
Entry | Database: PDB / ID: 7l28 | ||||||
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Title | Crystal structure of the catalytic domain of human PDE3A bound to Trequinsin | ||||||
![]() | cGMP-inhibited 3',5'-cyclic phosphodiesterase A | ||||||
![]() | HYDROLASE/HYDROLASE INHIBITOR / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex | ||||||
Function / homology | ![]() 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 / 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 ...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 / 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 / cellular response to transforming growth factor beta stimulus / cAMP-mediated signaling / apoptotic signaling pathway / lipid metabolic process / G alpha (s) signalling events / response to xenobiotic stimulus / G protein-coupled receptor signaling pathway / negative regulation of apoptotic process / membrane / metal ion binding / cytosol Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | Horner, S.W. / Garvie, C. | ||||||
![]() | ![]() Title: Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase. Authors: Colin W Garvie / Xiaoyun Wu / Malvina Papanastasiou / Sooncheol Lee / James Fuller / Gavin R Schnitzler / Steven W Horner / Andrew Baker / Terry Zhang / James P Mullahoo / Lindsay Westlake / ...Authors: Colin W Garvie / Xiaoyun Wu / Malvina Papanastasiou / Sooncheol Lee / James Fuller / Gavin R Schnitzler / Steven W Horner / Andrew Baker / Terry Zhang / James P Mullahoo / Lindsay Westlake / Stephanie H Hoyt / Marcus Toetzl / Matthew J Ranaghan / Luc de Waal / Joseph McGaunn / Bethany Kaplan / Federica Piccioni / Xiaoping Yang / Martin Lange / Adrian Tersteegen / Donald Raymond / Timothy A Lewis / Steven A Carr / Andrew D Cherniack / Christopher T Lemke / Matthew Meyerson / Heidi Greulich / ![]() ![]() 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 ...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. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 309.2 KB | Display | ![]() |
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PDB format | ![]() | 249.3 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 7kweC ![]() 7l27C ![]() 7l29C ![]() 7lrcC ![]() 7lrdC ![]() 7lreC ![]() 1so2S S: Starting model for refinement C: citing same article ( |
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Similar structure data |
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Assembly
Deposited unit | ![]()
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Unit cell |
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Noncrystallographic symmetry (NCS) | NCS domain:
NCS domain segments: Component-ID: _ / Beg auth comp-ID: LYS / Beg label comp-ID: LYS / Refine code: _
NCS ensembles :
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Components
-Protein , 1 types, 4 molecules ABCD
#1: Protein | Mass: 43169.121 Da / Num. of mol.: 4 / Fragment: Catalytic domain Source method: isolated from a genetically manipulated source Details: N-terminal glycine from cleavage with TEV protease. Residues 780 to 800 replaced with GGSGGS linker. Residues 1029 to 1067 replaced with GGSGGS linker. Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: Q14432, 3',5'-cyclic-nucleotide phosphodiesterase |
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-Non-polymers , 5 types, 123 molecules ![](data/chem/img/XKG.gif)
![](data/chem/img/MN.gif)
![](data/chem/img/MG.gif)
![](data/chem/img/ACT.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/MN.gif)
![](data/chem/img/MG.gif)
![](data/chem/img/ACT.gif)
![](data/chem/img/HOH.gif)
#2: Chemical | ChemComp-XKG / ( #3: Chemical | ChemComp-MN / #4: Chemical | ChemComp-MG / #5: Chemical | ChemComp-ACT / #6: Water | ChemComp-HOH / | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 2.27 Å3/Da / Density % sol: 45.91 % |
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Crystal grow | Temperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 5.9 / Details: MES, PEG 3350, calcium acetate / PH range: 5.7 - 6.1 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Diffraction source | Source: ![]() ![]() ![]() | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Detector | Type: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jul 26, 2018 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation wavelength | Wavelength: 0.976251 Å / Relative weight: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection | Resolution: 2.2→46.29 Å / Num. obs: 77869 / % possible obs: 98.2 % / Redundancy: 3.293 % / Biso Wilson estimate: 55.784 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.045 / Rrim(I) all: 0.054 / Χ2: 1.003 / Net I/σ(I): 14.54 / Num. measured all: 256435 / Scaling rejects: 147 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection shell | Diffraction-ID: 1
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Processing
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Refinement | Method to determine structure: ![]() Starting model: 1SO2 Resolution: 2.2→46.29 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.934 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.364 / ESU R Free: 0.24 / Stereochemistry target values: MAXIMUM LIKELIHOOD Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso max: 147.79 Å2 / Biso mean: 59.439 Å2 / Biso min: 30 Å2
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Refinement step | Cycle: final / Resolution: 2.2→46.29 Å
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Refine LS restraints |
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Refine LS restraints NCS | Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05
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LS refinement shell | Resolution: 2.204→2.261 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
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