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- PDB-8wkf: Rational Design of Highly Selective PDE5 inhibitors for the Treat... -

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Basic information

Entry
Database: PDB / ID: 8wkf
TitleRational Design of Highly Selective PDE5 inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis
ComponentscGMP-specific 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE/INHIBITOR / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


3',5'-cyclic-GMP phosphodiesterase / RHOBTB1 GTPase cycle / cGMP catabolic process / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / Smooth Muscle Contraction / : ...3',5'-cyclic-GMP phosphodiesterase / RHOBTB1 GTPase cycle / cGMP catabolic process / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / Smooth Muscle Contraction / : / 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 / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / GAF-like domain superfamily
Similarity search - Domain/homology
: / cGMP-specific 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsZhang, F.C. / Huang, Y.Y.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21977127 China
National Natural Science Foundation of China (NSFC)22077143 China
CitationJournal: To Be Published
Title: Rational Design of Highly Selective PDE5 inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis
Authors: Zhang, F.C. / Huang, Y.Y.
History
DepositionSep 27, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release

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Structure visualization

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)39,0324
Polymers38,4781
Non-polymers5543
Water1,802100
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)74.428, 74.428, 131.478
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 / cGMP-binding cGMP-specific phosphodiesterase / CGB-PDE


Mass: 38478.227 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: SMILES:ClC1=CC(CC2=NC(C=C(/C=C/C(O)=O)C=C3)=C3C(N2)=O)=C(NCC4=CC=CC(F)=C4)C=C1
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE5A, PDE5 / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: O76074, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-WD3 / 3-[2-[[5-chloranyl-2-[(3-fluorophenyl)methylamino]phenyl]methyl]-4-oxidanylidene-3~{H}-quinazolin-7-yl]prop-2-enoic acid


Mass: 463.888 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H19ClFN3O3 / Feature type: SUBJECT OF INVESTIGATION
#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


Mass: 18.015 Da / Num. of mol.: 100 / 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: 2.73 Å3/Da / Density % sol: 54.98 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.2 M magnesium sulfate, 0.1 M sodium cacodylate, pH 6.5, 18% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.54056 Å
DetectorType: RIGAKU HyPix-3000 / Detector: PIXEL / Date: Oct 31, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54056 Å / Relative weight: 1
ReflectionResolution: 2.4→23.01 Å / Num. obs: 17052 / % possible obs: 99.9 % / Redundancy: 8.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.085 / Net I/σ(I): 17.1
Reflection shellResolution: 2.4→2.49 Å / Rmerge(I) obs: 0.705 / Num. unique obs: 1757 / CC1/2: 0.792 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.11refinement
CrysalisProdata reduction
CrysalisProdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→23.01 Å / Cross valid method: NONE
RfactorNum. reflection% reflection
Rfree0.2479 --
Rwork0.1955 --
obs-16995 99.9 %
Refinement stepCycle: LAST / Resolution: 2.4→23.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2357 0 35 100 2492

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