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- PDB-8bpy: X-RAY STRUCTURE OF PDE9A IN COMPLEX WITH Inhibitor 13A -

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Basic information

Entry
Database: PDB / ID: 8bpy
TitleX-RAY STRUCTURE OF PDE9A IN COMPLEX WITH Inhibitor 13A
ComponentsHigh affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
KeywordsHYDROLASE / PDE9A / inhibitor
Function / homology
Function and homology information


cGMP metabolic process / negative regulation of neural precursor cell proliferation / 3',5'-cyclic-GMP phosphodiesterase / positive regulation of cardiac muscle hypertrophy / cGMP catabolic process / cGMP effects / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase activity / positive regulation of long-term synaptic potentiation / sarcolemma ...cGMP metabolic process / negative regulation of neural precursor cell proliferation / 3',5'-cyclic-GMP phosphodiesterase / positive regulation of cardiac muscle hypertrophy / cGMP catabolic process / cGMP effects / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase activity / positive regulation of long-term synaptic potentiation / sarcolemma / ruffle membrane / perikaryon / perinuclear region of cytoplasm / Golgi apparatus / endoplasmic reticulum / signal transduction / nucleoplasm / identical protein binding / metal ion binding / plasma membrane / 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. / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain
Similarity search - Domain/homology
Chem-R4I / High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.3 Å
AuthorsSteuber, H.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: BAY-7081: A Potent, Selective, and Orally Bioavailable Cyanopyridone-Based PDE9A Inhibitor.
Authors: Meibom, D. / Micus, S. / Andreevski, A.L. / Anlauf, S. / Bogner, P. / von Buehler, C.J. / Dieskau, A.P. / Dreher, J. / Eitner, F. / Fliegner, D. / Follmann, M. / Gericke, K.M. / Maassen, S. ...Authors: Meibom, D. / Micus, S. / Andreevski, A.L. / Anlauf, S. / Bogner, P. / von Buehler, C.J. / Dieskau, A.P. / Dreher, J. / Eitner, F. / Fliegner, D. / Follmann, M. / Gericke, K.M. / Maassen, S. / Meyer, J. / Schlemmer, K.H. / Steuber, H. / Tersteegen, A. / Wunder, F.
History
DepositionNov 18, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 28, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 4, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 2.0Jan 11, 2023Group: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Non-polymer description / Structure summary
Category: chem_comp / database_PDB_caveat ...chem_comp / database_PDB_caveat / entity / pdbx_entity_nonpoly / pdbx_validate_chiral
Item: _chem_comp.formula / _chem_comp.name ..._chem_comp.formula / _chem_comp.name / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 2.1May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
B: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,0269
Polymers74,3342
Non-polymers6927
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2190 Å2
ΔGint-82 kcal/mol
Surface area26790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)222.423, 222.423, 120.257
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422

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Components

#1: Protein High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A


Mass: 37166.953 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE9A / Production host: Escherichia coli (E. coli)
References: UniProt: O76083, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-R4I / (8~{S})-6-[2-(2,3-dihydroindol-1-yl)-2-oxidanylidene-ethyl]-4-(4-methylphenyl)-2-oxidanylidene-8-propyl-1,5,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile


Mass: 466.574 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H30N4O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Nonpolymer detailsLIGAND ISOPROPYL GROUP NOT FULLY DEFINED BY ELECTRON DENSITY. NO LIGAND BOUND TO CHAIN B.

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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: 5 Å3/Da / Density % sol: 75.41 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 35% PP 5/4, 0.2 M KCl, 50 mM Hepes pH 7.25

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.918409 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 26, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918409 Å / Relative weight: 1
ReflectionResolution: 3.3→50 Å / Num. obs: 22982 / % possible obs: 99.6 % / Redundancy: 8.8 % / CC1/2: 0.998 / Net I/σ(I): 12.1
Reflection shellResolution: 3.3→3.49 Å / Num. unique obs: 3601 / CC1/2: 0.739

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Processing

Software
NameVersionClassification
REFMAC5.8.0123refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse structure

Resolution: 3.3→49.74 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.889 / SU B: 35.017 / SU ML: 0.525 / Cross valid method: THROUGHOUT / ESU R: 1.839 / ESU R Free: 0.511 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.31232 1149 5 %RANDOM
Rwork0.24649 ---
obs0.24974 21832 99.59 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 131.928 Å2
Baniso -1Baniso -2Baniso -3
1-4.01 Å2-0 Å20 Å2
2--4.01 Å2-0 Å2
3----8.01 Å2
Refinement stepCycle: LAST / Resolution: 3.3→49.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5160 0 41 0 5201
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0195331
X-RAY DIFFRACTIONr_bond_other_d0.0020.024978
X-RAY DIFFRACTIONr_angle_refined_deg1.5631.9597232
X-RAY DIFFRACTIONr_angle_other_deg1.0193.00111431
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0515628
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.88524.242264
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.14615932
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.1981532
X-RAY DIFFRACTIONr_chiral_restr0.0820.2786
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0215948
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021235
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_it9.76313.1412518
X-RAY DIFFRACTIONr_mcbond_other9.76513.1382517
X-RAY DIFFRACTIONr_mcangle_it15.4219.663143
X-RAY DIFFRACTIONr_mcangle_other15.41719.6643144
X-RAY DIFFRACTIONr_scbond_it8.04313.4812813
X-RAY DIFFRACTIONr_scbond_other8.04213.4792814
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other13.00220.0734087
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.3→3.38 Å
RfactorNum. reflection% reflection
Rfree0.466 81 -
Rwork0.404 1557 -
obs--97.27 %

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