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- PDB-4ia0: Crystal structure of the PDE5A1 catalytic domain in complex with ... -

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Basic information

Entry
Database: PDB / ID: 4ia0
TitleCrystal structure of the PDE5A1 catalytic domain in complex with novel inhibitors
ComponentscGMP-specific 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / 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 / positive regulation of cardiac muscle hypertrophy / cGMP catabolic process / 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 / positive regulation of cardiac muscle hypertrophy / cGMP catabolic process / cGMP effects / 3',5'-cyclic-GMP phosphodiesterase activity / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / Smooth Muscle Contraction / T cell proliferation / negative regulation of T cell proliferation / signal transduction / metal ion binding / cytosol
Similarity search - Function
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / GAF domain / 3'5'-cyclic nucleotide phosphodiesterase / Domain present in phytochromes and cGMP-specific phosphodiesterases. / 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. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / GAF domain / 3'5'-cyclic nucleotide phosphodiesterase / Domain present in phytochromes and cGMP-specific phosphodiesterases. / 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 / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-5BB / cGMP-specific 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.17 Å
AuthorsRen, J. / Chen, T. / Xu, Y.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Exploration of the 5-bromopyrimidin-4(3H)-ones as potent inhibitors of PDE5.
Authors: Gong, X. / Wang, G. / Ren, J. / Liu, Z. / Wang, Z. / Chen, T. / Yang, X. / Jiang, X. / Shen, J. / Jiang, H. / Aisa, H.A. / Xu, Y. / Li, J.
History
DepositionDec 5, 2012Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jan 1, 2014Provider: 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)40,7504
Polymers40,0911
Non-polymers6593
Water1,27971
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)74.430, 74.430, 131.260
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

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


Mass: 40091.090 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 535-860
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE5, PDE5A / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: O76074, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-5BB / 5-bromo-2-{2-ethoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-octylpyrimidin-4(3H)-one


Mass: 569.555 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H37BrN4O4S
#3: Chemical ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 71 / Source method: isolated from a natural source / Formula: H2O

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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: 2.62 Å3/Da / Density % sol: 53.02 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 19-20%(w/v) PEG 3350, 200mM MgSO4, 100mM Tris-HCl, pH 7.5, vapor diffusion, hanging drop, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.979 Å
DetectorType: ADSC Quantum Q315r / Detector: CCD / Date: Jul 10, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.17→36.201 Å / Num. obs: 22836 / % possible obs: 99.7 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 38.76 Å2 / Rmerge(I) obs: 0.048 / Net I/σ(I): 22.36
Reflection shell

Diffraction-ID: 1

Resolution (Å)Highest resolution (Å)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
2.17-2.230.3730.3394.547934166416630.38299.9
2.23-2.290.3170.2745.557717161116100.30999.9
2.29-2.350.2550.2296.57539157815740.25899.7
2.35-2.430.2140.2057.327408154615460.231100
2.43-2.510.2020.1758.457122148314830.197100
2.51-2.590.1430.12711.426936145314490.14399.7
2.59-2.690.110.10313.936692139613960.116100
2.69-2.80.0960.09115.996444134913480.10399.9
2.8-2.930.080.07518.766135129112880.08599.8
2.93-3.070.0640.06621.65884125412520.07499.8
3.07-3.230.0510.04827.965526118311820.05499.9
3.23-3.430.0360.03933.55091109710930.04599.6
3.43-3.670.0290.03338.294832105810530.03899.5
3.67-3.960.0260.03142.18450510009900.03599
3.96-4.340.0210.02548.2242939059040.02899.9
4.34-4.850.0160.02252.339538388380.025100
4.85-5.60.0180.02248.9735287527520.025100
5.6-6.860.0190.02348.6929496336330.026100
6.86-9.70.0130.01755.9922105085060.0299.6
9.70.0110.01558.2510543102760.01889

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.17 Å36.2 Å
Translation2.17 Å36.2 Å

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASER2.1.4phasing
PHENIX1.8_1069refinement
PDB_EXTRACT3.11data extraction
Blu-Icedata collection
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.17→36.201 Å / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8113 / SU ML: 0.2 / σ(F): 2.02 / Phase error: 25.36 / Stereochemistry target values: MLHL
RfactorNum. reflection% reflection
Rfree0.2527 686 3 %
Rwork0.2143 --
obs0.2154 22835 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 96.51 Å2 / Biso mean: 39.0783 Å2 / Biso min: 23.23 Å2
Refinement stepCycle: LAST / Resolution: 2.17→36.201 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2359 0 37 71 2467
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082448
X-RAY DIFFRACTIONf_angle_d1.0973307
X-RAY DIFFRACTIONf_chiral_restr0.073372
X-RAY DIFFRACTIONf_plane_restr0.005416
X-RAY DIFFRACTIONf_dihedral_angle_d17.034923
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 5

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1702-2.33770.3081350.239743524487100
2.3377-2.57290.28571360.238743984534100
2.5729-2.94510.25351350.235443654500100
2.9451-3.70990.29151380.217944484586100
3.7099-36.20620.20591420.19234586472899

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