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- PDB-7kwe: Crystal structure of the catalytic domain of human PDE3A bound to... -
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Open data
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Basic information
Entry | Database: PDB / ID: 7kwe | ||||||
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Title | Crystal structure of the catalytic domain of human PDE3A bound to DNMDP | ||||||
![]() | cGMP-inhibited 3',5'-cyclic phosphodiesterase A | ||||||
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Function / homology | ![]() cGMP-inhibited cyclic-nucleotide phosphodiesterase activity / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() 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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Download
PDBx/mmCIF format | ![]() | 611.5 KB | Display | ![]() |
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PDB format | ![]() | 505.4 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 7l27C ![]() 7l28C ![]() 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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Links
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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: 0 / Refine code: 0
NCS ensembles :
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Components
-Protein , 1 types, 4 molecules ADCB
#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, ![]() |
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-Non-polymers , 5 types, 375 molecules ![](data/chem/img/X5M.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-X5M / ( #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: 2.2 Å3/Da / Density % sol: 44.01 % |
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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: Jun 1, 2018 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength![]() |
Reflection | Resolution: 2→47.7 Å / Num. obs: 187181 / % possible obs: 94.3 % / Redundancy: 1.8 % / CC1/2: 0.998 / Rrim(I) all: 0.057 / Net I/σ(I): 10.79 |
Reflection shell | Resolution: 2→2.11 Å / Redundancy: 1.7 % / Mean I/σ(I) obs: 1.47 / Num. unique obs: 29075 / CC1/2: 0.64 / Rrim(I) all: 0.747 / % possible all: 91.7 |
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Processing
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Refinement | Method to determine structure![]() ![]() Starting model: 1SO2 Resolution: 2→47.7 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.956 / SU B: 10.709 / SU ML: 0.144 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.194 / ESU R Free: 0.161 / Stereochemistry target values: MAXIMUM LIKELIHOOD Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
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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: 138.33 Å2 / Biso mean: 49.716 Å2 / Biso min: 23.67 Å2
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Refinement step | Cycle: final / Resolution: 2→47.7 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: 2.002→2.054 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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