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- PDB-4qge: phosphodiesterase-9A in complex with inhibitor WYQ-C36D -

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Basic information

Entry
Database: PDB / ID: 4qge
Titlephosphodiesterase-9A in complex with inhibitor WYQ-C36D
ComponentsPhosphodiesterase 9A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PDE9 catalytic domain / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


cGMP metabolic process / 3',5'-cyclic-GMP phosphodiesterase / cGMP catabolic process / positive regulation of cardiac muscle hypertrophy / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP-mediated signaling / sarcolemma / ruffle membrane / perinuclear region of cytoplasm ...cGMP metabolic process / 3',5'-cyclic-GMP phosphodiesterase / cGMP catabolic process / positive regulation of cardiac muscle hypertrophy / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP-mediated signaling / sarcolemma / ruffle membrane / perinuclear region of cytoplasm / Golgi apparatus / endoplasmic reticulum / metal ion binding
Similarity search - Function
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic 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. / Metal dependent phosphohydrolases with conserved 'HD' motif. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic 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. / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-35O / High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A / High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
Similarity search - Component
Biological speciesPan troglodytes (chimpanzee)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsShao, Y.-X. / Huang, M. / Cui, W. / Ke, H.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of a Phosphodiesterase 9A Inhibitor as a Potential Hypoglycemic Agent.
Authors: Shao, Y.X. / Huang, M. / Cui, W. / Feng, L.J. / Wu, Y. / Cai, Y. / Li, Z. / Zhu, X. / Liu, P. / Wan, Y. / Ke, H. / Luo, H.B.
History
DepositionMay 22, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 10, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 14, 2015Group: Database references
Revision 1.2Apr 3, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / 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 / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_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 / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Phosphodiesterase 9A
B: Phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,5508
Polymers123,5782
Non-polymers9726
Water5,386299
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Phosphodiesterase 9A
hetero molecules

B: Phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,5508
Polymers123,5782
Non-polymers9726
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_655-x+3/2,y+1/2,-z+1/41
Buried area1920 Å2
ΔGint-109 kcal/mol
Surface area27870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.580, 103.580, 268.657
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Phosphodiesterase 9A


Mass: 61789.078 Da / Num. of mol.: 2 / Fragment: catalytic domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Pan troglodytes (chimpanzee) / Gene: PDE9A / References: UniProt: K7AGW3, UniProt: H2QL32*PLUS
#2: Chemical ChemComp-35O / N~2~-(1-cyclopentyl-4-oxo-4,7-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-methoxyphenyl)-D-alaninamide


Mass: 396.443 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H24N6O3
#3: Chemical ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 299 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.92 Å3/Da / Density % sol: 57.81 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: The crystals of PDE9A2 were grown by using hanging drop vapor diffusion method. The PDE9A2 (181 506) (8-10 mg/mL) in a buffer of 50 mM NaCl, 20 mM Tris HCl, pH 7.5, 1 mM -mercaptoethanol, ...Details: The crystals of PDE9A2 were grown by using hanging drop vapor diffusion method. The PDE9A2 (181 506) (8-10 mg/mL) in a buffer of 50 mM NaCl, 20 mM Tris HCl, pH 7.5, 1 mM -mercaptoethanol, and 1 mM EDTA was mixed with 2 mM IBMX overnight before setting-up of crystallization against the well buffer of 0.1 M HEPES (pH 7.5), 3.0 M sodium formate at 4 C. Crystals of the PDE9-3r complex were prepared by soaking PDE9-IBMX cocrystals in the crystallization buffer plus 2 mM 3r at 25oC for 3 days., VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.05 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.05 Å / Relative weight: 1
ReflectionResolution: 2→30 Å / Num. obs: 91112 / % possible obs: 91.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 10.5 % / Rmerge(I) obs: 0.065 / Net I/σ(I): 23

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
AMoREphasing
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDE9 catalytic domain

Resolution: 2→30 Å / σ(F): 0 / σ(I): 0
RfactorNum. reflectionSelection details
Rfree0.268 9098 random
Rwork0.241 --
obs-91068 -
Refinement stepCycle: LAST / Resolution: 2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5304 0 62 299 5665
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg1.2

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