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- PDB-3sie: Crystal structure of the PDE5A1 catalytic domain in complex with ... -

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Basic information

Entry
Database: PDB / ID: 3sie
TitleCrystal structure of the PDE5A1 catalytic domain in complex with novel inhibitors
ComponentscGMP-specific 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PDE5A 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 / 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-nucleotide phosphodiesterase activity / cGMP binding / Smooth Muscle Contraction / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / T cell proliferation / negative regulation of 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-5BO / cGMP-specific 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.93 Å
AuthorsChen, T.T. / Chen, T. / Xu, Y.C.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Utilization of Halogen Bond in Lead Optimization: A Case Study of Rational Design of Potent Phosphodiesterase Type 5 (PDE5) Inhibitors.
Authors: Xu, Z. / Liu, Z. / Chen, T. / Chen, T.T. / Wang, Z. / Tian, G. / Shi, J. / Wang, X. / Lu, Y. / Yan, X. / Wang, G. / Jiang, H. / Chen, K. / Wang, S. / Xu, Y. / Shen, J. / Zhu, W.
History
DepositionJun 17, 2011Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Aug 24, 2011Provider: repository / Type: Initial release
Revision 1.1Jun 27, 2012Group: Experimental preparation
Revision 1.2Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)81,1814
Polymers80,1822
Non-polymers9992
Water8,917495
1
A: cGMP-specific 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,5912
Polymers40,0911
Non-polymers4991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: cGMP-specific 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,5912
Polymers40,0911
Non-polymers4991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.180, 94.120, 114.260
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein cGMP-specific 3',5'-cyclic phosphodiesterase / PDE5A1 / cGMP-binding cGMP-specific phosphodiesterase / CGB-PDE


Mass: 40091.090 Da / Num. of mol.: 2 / 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-5BO / 5-bromo-6-ethyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]-2-propoxyphenyl}pyrimidin-4(3H)-one


Mass: 499.422 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H27BrN4O4S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 495 / 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: 2.19 Å3/Da / Density % sol: 43.72 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 16% PEG 3350, 0.1M Sodium acetate, pH 4.6, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 13, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.93→47.06 Å / Num. obs: 53386

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHENIX1.7_650refinement
PDB_EXTRACT3.1data extraction
ADSCQuantumdata collection
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.93→47.06 Å / Occupancy max: 1 / Occupancy min: 0.5 / SU ML: 0.21 / σ(F): 1.99 / Phase error: 22.74 / Stereochemistry target values: MLHL
RfactorNum. reflection% reflection
Rfree0.2348 1601 3 %
Rwork0.1913 51785 -
obs0.1926 53386 99.63 %
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 40.626 Å2 / ksol: 0.333 e/Å3
Displacement parametersBiso max: 59.64 Å2 / Biso mean: 26.0306 Å2 / Biso min: 10.33 Å2
Baniso -1Baniso -2Baniso -3
1-1.0466 Å20 Å2-0 Å2
2--2.283 Å20 Å2
3----3.3296 Å2
Refinement stepCycle: LAST / Resolution: 1.93→47.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4583 0 60 495 5138
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084752
X-RAY DIFFRACTIONf_angle_d1.16454
X-RAY DIFFRACTIONf_chiral_restr0.068757
X-RAY DIFFRACTIONf_plane_restr0.005809
X-RAY DIFFRACTIONf_dihedral_angle_d12.7291681
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.93-1.99230.28031440.223146444788100
1.9923-2.06350.27141430.200946434786100
2.0635-2.14610.26411450.195146844829100
2.1461-2.24380.27041430.22544619476298
2.2438-2.3620.30651410.24074581472298
2.362-2.510.26181460.19246894835100
2.51-2.70380.25431450.19146964841100
2.7038-2.97590.23771460.188947394885100
2.9759-3.40640.21931470.183447304877100
3.4064-4.29120.1991470.172747774924100
4.2912-47.0740.20511540.181749835137100

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