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- PDB-4md6: Crystal structure of PDE5 in complex with inhibitor 5R -

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Basic information

Entry
Database: PDB / ID: 4md6
TitleCrystal structure of PDE5 in complex with inhibitor 5R
ComponentscGMP-specific 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / protein-inhibitor complex / phosphodiesterase / PDE5 inhibitor / 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 / relaxation of cardiac muscle / RHOBTB1 GTPase cycle / 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 / relaxation of cardiac muscle / RHOBTB1 GTPase cycle / positive regulation of cardiac muscle hypertrophy / cGMP catabolic process / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / Smooth Muscle Contraction / 3',5'-cyclic-GMP phosphodiesterase activity / 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
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 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. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 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. / Domain present in phytochromes and cGMP-specific phosphodiesterases. / 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-24E / cGMP-specific 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsCui, W. / Huang, M. / Shao, Y. / Luo, H.
CitationJournal: Biochem Pharmacol / Year: 2014
Title: Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure.
Authors: Shang, N.N. / Shao, Y.X. / Cai, Y.H. / Guan, M. / Huang, M. / Cui, W. / He, L. / Yu, Y.J. / Huang, L. / Li, Z. / Bu, X.Z. / Ke, H. / Luo, H.B.
History
DepositionAug 22, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 9, 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)38,3485
Polymers37,7891
Non-polymers5594
Water1,27971
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.106, 74.106, 132.344
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 37788.531 Da / Num. of mol.: 1 / Fragment: catalytic domain (UNP residues 535-860)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE5A, PDE5 / Plasmid: pET15 / Production host: Escherichia coli (E. coli)
References: UniProt: O76074, 3',5'-cyclic-GMP phosphodiesterase

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Non-polymers , 5 types, 75 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-24E / 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one


Mass: 373.424 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H15NO3S
#4: Chemical ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / 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: 2.78 Å3/Da / Density % sol: 55.69 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 6-10 mg/mL unliganded PDE5A1 in storage buffer (50 mM sodium chloride, 20 mM Tris-HCl, pH 7.5, 1 mM BME, 1 mM EDTA) against 0.2 M magnesium sulfate, 0.1 M sodium cacodylate, pH 6.5, 18% ...Details: 6-10 mg/mL unliganded PDE5A1 in storage buffer (50 mM sodium chloride, 20 mM Tris-HCl, pH 7.5, 1 mM BME, 1 mM EDTA) against 0.2 M magnesium sulfate, 0.1 M sodium cacodylate, pH 6.5, 18% PEG3350, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 20, 2013
RadiationMonochromator: Rosenbaum-Rock double crystal sagittal focusing
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→30 Å / Num. all: 29180 / Num. obs: 29180 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 22.8 % / Rmerge(I) obs: 0.065 / Net I/σ(I): 14
Reflection shellHighest resolution: 2 Å

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Processing

Software
NameClassification
HKL-2000data collection
AMoREphasing
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→30 Å / Occupancy max: 1 / Occupancy min: 1 / Isotropic thermal model: ISOTROPIC / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2475 2830 9.7 %RANDOM
Rwork0.217 25604 --
obs0.217 28434 97.7 %-
Solvent computationBsol: 60.18 Å2
Displacement parametersBiso max: 96.61 Å2 / Biso mean: 47.796 Å2 / Biso min: 24.68 Å2
Baniso -1Baniso -2Baniso -3
1-1.02 Å20 Å20 Å2
2--1.02 Å20 Å2
3----2.04 Å2
Refinement stepCycle: LAST / Resolution: 2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2418 0 34 71 2523
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_mcbond_it1.4751.5
X-RAY DIFFRACTIONc_scbond_it2.1752
X-RAY DIFFRACTIONc_mcangle_it2.3262
X-RAY DIFFRACTIONc_scangle_it3.1212.5
X-RAY DIFFRACTIONc_bond_d0.0052
X-RAY DIFFRACTIONc_angle_deg1.1
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1CNS_TOPPAR:protein_rep.param
X-RAY DIFFRACTION2CNS_TOPPAR:water_rep.param
X-RAY DIFFRACTION3CNS_TOPPAR:dna-rna_rep.param
X-RAY DIFFRACTION45r.param
X-RAY DIFFRACTION5ion.param

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