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- PDB-7far: Crystal structure of PDE5A in complex with inhibitor L12 -

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Basic information

Entry
Database: PDB / ID: 7far
TitleCrystal structure of PDE5A in complex with inhibitor L12
ComponentscGMP-specific 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE/INHIBITOR / 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-2VI / cGMP-specific 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.40006470991 Å
AuthorsWu, D. / Huang, Y.Y. / Luo, H.B.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81872727 China
National Natural Science Foundation of China (NSFC)81602955 China
National Natural Science Foundation of China (NSFC)21702238 China
CitationJournal: Acta Pharm Sin B / Year: 2022
Title: Free energy perturbation (FEP)-guided scaffold hopping.
Authors: Wu, D. / Zheng, X. / Liu, R. / Li, Z. / Jiang, Z. / Zhou, Q. / Huang, Y. / Wu, X.N. / Zhang, C. / Huang, Y.Y. / Luo, H.B.
History
DepositionJul 7, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 18, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

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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)40,8054
Polymers40,2661
Non-polymers5393
Water1,02757
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area80 Å2
ΔGint-33 kcal/mol
Surface area13430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.917, 73.917, 132.251
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Space group name HallP312"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3
#4: x-y,-y,-z+2/3
#5: -x,-x+y,-z+1/3
#6: y,x,-z

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Components

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


Mass: 40266.242 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 (bacteria)
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-2VI / 5-[bis(fluoranyl)methoxy]-2-[(4-chlorophenyl)methyl]-10-(3-methoxypropyl)-3,10-diazatricyclo[6.4.1.0^{4,13}]trideca-1,4(13),5,7-tetraen-9-one


Mass: 448.890 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H23ClF2N2O3 / 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: 2.59 Å3/Da / Density % sol: 52.51 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.2 M magnesium sulfate, 0.1 M sodium cacodylate, pH 6.5, 17% 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: Jan 4, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54056 Å / Relative weight: 1
ReflectionResolution: 2.4→23.8 Å / Num. obs: 16912 / % possible obs: 99.98 % / Redundancy: 8.7 % / Biso Wilson estimate: 42.9860746845 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 26.4
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 7.2 % / Rmerge(I) obs: 0.73 / Mean I/σ(I) obs: 3.4 / Num. unique obs: 1624 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.10_2155refinement
CrysalisProdata reduction
CrysalisProdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4MD6

4md6


Resolution: 2.40006470991→23.7999108169 Å / SU ML: 0.358807461027 / Cross valid method: NONE / σ(F): 1.36566493008 / Phase error: 29.5818111326
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.249946221896 837 4.94944119212 %
Rwork0.212773636809 16074 -
obs0.214795705707 16911 99.9704421849 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 50.2141933494 Å2
Refinement stepCycle: LAST / Resolution: 2.40006470991→23.7999108169 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2357 0 33 57 2447
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.009001382920322436
X-RAY DIFFRACTIONf_angle_d1.175054382393291
X-RAY DIFFRACTIONf_chiral_restr0.0499571962668370
X-RAY DIFFRACTIONf_plane_restr0.00615778406436438
X-RAY DIFFRACTIONf_dihedral_angle_d17.74570884081484
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4001-2.55030.3479347498291340.3033040463482626X-RAY DIFFRACTION99.9637812387
2.5503-2.74690.3470843974641270.2788424829172664X-RAY DIFFRACTION100
2.7469-3.02290.3250946877871360.2703470853282623X-RAY DIFFRACTION100
3.0229-3.45910.2863668524141260.228894969232677X-RAY DIFFRACTION100
3.4591-4.35380.25589014681400.1880812246962697X-RAY DIFFRACTION100
4.3538-23.790.1920072661821740.1739427381932787X-RAY DIFFRACTION99.8650927487

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