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- PDB-8w4t: Crystal structure of PDE5A in complex with a novel inhibitor -

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Basic information

Entry
Database: PDB / ID: 8w4t
TitleCrystal structure of PDE5A in complex with a novel inhibitor
ComponentscGMP-specific 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PDE5A / Inhibitor / Complex structure / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of oocyte development / 3',5'-cyclic-GMP phosphodiesterase / regulation of nitric oxide mediated signal transduction / negative regulation of cardiac muscle contraction / oocyte development / RHOBTB1 GTPase cycle / relaxation of cardiac muscle / cGMP catabolic process / positive regulation of cardiac muscle hypertrophy / cGMP effects ...positive regulation of oocyte development / 3',5'-cyclic-GMP phosphodiesterase / regulation of nitric oxide mediated signal transduction / negative regulation of cardiac muscle contraction / oocyte development / RHOBTB1 GTPase cycle / relaxation of cardiac muscle / cGMP catabolic process / positive regulation of cardiac muscle hypertrophy / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / Smooth Muscle Contraction / 3',5'-cyclic-AMP phosphodiesterase activity / negative regulation of T cell proliferation / T cell proliferation / cAMP-mediated signaling / metal ion binding / cytosol
Similarity search - Function
3'5'-cyclic nucleotide phosphodiesterase / 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. / GAF domain / Domain present in phytochromes and cGMP-specific phosphodiesterases. / GAF domain ...3'5'-cyclic nucleotide phosphodiesterase / 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. / GAF domain / Domain present in phytochromes and cGMP-specific phosphodiesterases. / GAF domain / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain
Similarity search - Domain/homology
Chem-VZF / cGMP-specific 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.199 Å
AuthorsLiu, J.Y. / Li, M.J. / Xu, Y.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors.
Authors: Liu, J. / Zhang, X. / Chen, G. / Shao, Q. / Zou, Y. / Li, Z. / Su, H. / Li, M. / Xu, Y.
History
DepositionAug 24, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 22, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: cGMP-specific 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,5974
Polymers40,0911
Non-polymers5063
Water1,02757
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)74.776, 74.776, 131.889
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

#1: Protein cGMP-specific 3',5'-cyclic phosphodiesterase / Phosphodiesterase type 5 / cGMP-binding cGMP-specific phosphodiesterase / CGB-PDE


Mass: 40091.090 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE5A, PDE5 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: O76074, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-VZF / 2-[bis(2-hydroxyethyl)amino]-6-[(4-methoxyphenyl)methylamino]-9-propan-2-yl-7~{H}-purin-8-one


Mass: 416.474 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H28N6O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 57 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.66 Å3/Da / Density % sol: 53.67 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 0.1 M Tris-HCl, 0.2 M MgSO4, 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 30, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.199→50 Å / Num. obs: 22346 / % possible obs: 100 % / Redundancy: 19 % / CC1/2: 0.99 / CC star: 0.997 / Rmerge(I) obs: 0.109 / Rpim(I) all: 0.026 / Rrim(I) all: 0.112 / Χ2: 0.989 / Net I/σ(I): 9.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
2.2-2.2414.72.54910720.7120.9120.6722.6380.946100
2.24-2.2817.41.55510890.830.9520.381.6020.981100
2.28-2.3218.72.01710980.9290.9820.4742.0730.947100
2.32-2.3719.51.76611070.9210.9790.4071.8130.954100
2.37-2.4219.71.46210830.9220.9790.3341.50.958100
2.42-2.4819.81.21111160.9640.9910.2761.2420.968100
2.48-2.5419.40.91910960.9660.9910.2110.9440.975100
2.54-2.6119.10.66610990.9780.9940.1550.6841.005100
2.61-2.6918.50.47811150.990.9970.1130.4910.976100
2.69-2.7719.20.38511180.9870.9970.090.3961.003100
2.77-2.8720.30.30811050.9910.9980.0690.3160.981100
2.87-2.9920.20.23710950.9930.9980.0530.2430.997100
2.99-3.1220.10.17611180.9970.9990.040.1810.987100
3.12-3.2919.70.11711050.9960.9990.0270.121.012100
3.29-3.4918.40.09111260.9970.9990.0220.0941.025100
3.49-3.7619.60.07611320.9970.9990.0180.0781.062100
3.76-4.1420.10.06511290.9980.9990.0150.0671.081100
4.14-4.7419.40.05811560.99810.0140.061.09100
4.74-5.9718.20.05411500.9960.9990.0130.0561.026100
5.97-5017.70.04212370.9980.9990.0110.0430.79399.4

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-3000data scaling
HKL-3000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.199→32.524 Å / SU ML: 0.32 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 26.96 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2684 1000 4.69 %
Rwork0.2202 --
obs0.2224 21324 95.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.199→32.524 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2324 0 32 57 2413
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022399
X-RAY DIFFRACTIONf_angle_d0.4283247
X-RAY DIFFRACTIONf_dihedral_angle_d7.2831457
X-RAY DIFFRACTIONf_chiral_restr0.032375
X-RAY DIFFRACTIONf_plane_restr0.003410
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.199-2.31490.33341030.27812037X-RAY DIFFRACTION69
2.3149-2.45990.32451320.2762981X-RAY DIFFRACTION100
2.4599-2.64980.30131500.25912994X-RAY DIFFRACTION100
2.6498-2.91630.29971720.24832996X-RAY DIFFRACTION100
2.9163-3.33790.33921420.2383028X-RAY DIFFRACTION100
3.3379-4.2040.21421650.19893059X-RAY DIFFRACTION100
4.204-32.520.22511360.18243229X-RAY DIFFRACTION100

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