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- PDB-6acb: Crystal structure of PDE5 in complex with inhibitor LW1805 -

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Basic information

Entry
Database: PDB / ID: 6acb
TitleCrystal structure of PDE5 in complex with inhibitor LW1805
ComponentscGMP-specific 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PDE5 in complex with inhibitor LW1805 / 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 / 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-9T9 / cGMP-specific 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsWu, D. / Huang, Y.D. / Huang, Y.Y. / Luo, H.B.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China81602955 China
National Natural Science Foundation of China21702238 China
CitationJournal: J. Med. Chem. / Year: 2018
Title: Optimization of Chromeno[2,3- c]pyrrol-9(2 H)-ones as Highly Potent, Selective, and Orally Bioavailable PDE5 Inhibitors: Structure-Activity Relationship, X-ray Crystal Structure, and ...Title: Optimization of Chromeno[2,3- c]pyrrol-9(2 H)-ones as Highly Potent, Selective, and Orally Bioavailable PDE5 Inhibitors: Structure-Activity Relationship, X-ray Crystal Structure, and Pharmacodynamic Effect on Pulmonary Arterial Hypertension.
Authors: Wu, D. / Huang, Y. / Chen, Y. / Huang, Y.Y. / Geng, H. / Zhang, T. / Zhang, C. / Li, Z. / Guo, L. / Chen, J. / Luo, H.B.
History
DepositionJul 26, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 19, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 10, 2018Group: Data collection / Database references / Structure summary
Category: citation / entity
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _entity.formula_weight
Revision 1.2Nov 22, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.formula_weight / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,5365
Polymers37,7891
Non-polymers7474
Water81145
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: cGMP-specific 3',5'-cyclic phosphodiesterase
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area330 Å2
ΔGint-54 kcal/mol
Surface area14410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.577, 74.577, 132.092
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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE5A, PDE5 / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
References: UniProt: O76074, 3',5'-cyclic-GMP phosphodiesterase

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Non-polymers , 5 types, 49 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#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: Chemical ChemComp-9T9 / 3-[(2H-1,3-benzodioxol-5-yl)methyl]-8-fluoro-6-{[2-(4-methylpiperazin-1-yl)ethyl]amino}-1-(1,3-thiazol-2-yl)[1]benzopyrano[2,3-c]pyrrol-9(2H)-one


Mass: 561.627 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H28FN5O4S
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 45 / 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: 2.81 Å3/Da / Density % sol: 56.17 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1 M Cacodylate Sodium (pH6.5), 0.2 M MgSO4, 18% PEG3350, 2.5% ethanol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SEALED TUBE / Type: OXFORD DIFFRACTION NOVA / Wavelength: 1.5406 Å
DetectorType: OXFORD ONYX CCD / Detector: CCD / Date: Feb 10, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5406 Å / Relative weight: 1
ReflectionResolution: 2.8→24 Å / Num. obs: 10461 / % possible obs: 95.74 % / Redundancy: 7.9 % / Rmerge(I) obs: 0.132 / Net I/σ(I): 14.1
Reflection shellResolution: 2.8→2.9 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
CrysalisPro38.41data reduction
CrysalisPro38.41data scaling
PHASER1.1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4MD6

4md6


Resolution: 2.8→24 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.867 / SU B: 16.778 / SU ML: 0.316 / Cross valid method: THROUGHOUT / ESU R Free: 0.397 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26828 546 5.2 %RANDOM
Rwork0.1976 ---
obs0.20112 9913 95.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 41.812 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å2-0.01 Å2-0 Å2
2---0.02 Å20 Å2
3---0.06 Å2
Refinement stepCycle: 1 / Resolution: 2.8→24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2499 0 47 45 2591
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0192598
X-RAY DIFFRACTIONr_bond_other_d0.0020.022406
X-RAY DIFFRACTIONr_angle_refined_deg1.511.9433514
X-RAY DIFFRACTIONr_angle_other_deg1.00135591
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.9885306
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.59324.8125
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.53515474
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8371513
X-RAY DIFFRACTIONr_chiral_restr0.0840.2390
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022970
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02515
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.8214.0681230
X-RAY DIFFRACTIONr_mcbond_other2.8054.0631229
X-RAY DIFFRACTIONr_mcangle_it4.586.0771534
X-RAY DIFFRACTIONr_mcangle_other4.5866.0831535
X-RAY DIFFRACTIONr_scbond_it2.5844.5061366
X-RAY DIFFRACTIONr_scbond_other2.5834.5081367
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.3836.6331979
X-RAY DIFFRACTIONr_long_range_B_refined8.1648.8773067
X-RAY DIFFRACTIONr_long_range_B_other8.1548.9583061
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.8→2.873 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.345 42 -
Rwork0.3 693 -
obs--95.33 %

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