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- PDB-4gh6: Crystal structure of the PDE9A catalytic domain in complex with i... -

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Basic information

Entry
Database: PDB / ID: 4gh6
TitleCrystal structure of the PDE9A catalytic domain in complex with inhibitor 28
ComponentsHigh affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
KeywordsHYDROLASE/Hydrolase Inhibitor / PDE9A / HYDROLASE-Hydrolase Inhibitor complex
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-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP-mediated signaling ...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-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP-mediated signaling / 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
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-LUO / High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsHou, J. / Ke, H.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Structure-Based Discovery of Highly Selective Phosphodiesterase-9A Inhibitors and Implications for Inhibitor Design.
Authors: Meng, F. / Hou, J. / Shao, Y.X. / Wu, P.Y. / Huang, M. / Zhu, X. / Cai, Y. / Li, Z. / Xu, J. / Liu, P. / Luo, H.B. / Wan, Y. / Ke, H.
History
DepositionAug 7, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 3, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 14, 2012Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / 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_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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)78,5289
Polymers77,0932
Non-polymers1,4357
Water32418
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2500 Å2
ΔGint-111 kcal/mol
Surface area28270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.276, 104.276, 270.073
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 High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A


Mass: 38546.570 Da / Num. of mol.: 2 / Fragment: UNP residues 241-566
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE9A / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(codonplus)
References: UniProt: O76083, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-LUO / N-(4-methoxyphenyl)-N~2~-[1-(2-methylphenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-L-alaninamide


Mass: 418.448 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C22H22N6O3
#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.: 18 / 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: 4.76 Å3/Da / Density % sol: 74.17 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: PDE9A2 (15 mg/mL) in a buffer of 50 mM NaCl, 20 mM Tris.HCl pH 7.5, 1 mM beta-mercaptoethanol and 1 mM EDTA was mixed with 2 mM IBMX for 2h before setting-up of crystallization against the ...Details: PDE9A2 (15 mg/mL) in a buffer of 50 mM NaCl, 20 mM Tris.HCl pH 7.5, 1 mM beta-mercaptoethanol and 1 mM EDTA was mixed with 2 mM IBMX for 2h before setting-up of crystallization against the well buffer of 2.0 M Na formate, 0.1 M HEPES pH 7.5, 5% xylitol at 4C. The PDE9A-IBMX complex crystals were formed after 1d and reached the maximum size in 2 weeks. Crystals of the PDE9A-28 complex were prepared by soaking PDE9-IBMX co-crystals in the crystallization buffer plus 5 mM 28 at 25C for 3 days, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-17A / Wavelength: 1 Å
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→30 Å / Num. obs: 41120 / % possible obs: 99.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.093 / Net I/σ(I): 17.4

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Processing

Software
NameClassification
AMoREphasing
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→30 Å / Isotropic thermal model: isotropic / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.245 3897 Random
Rwork0.212 --
obs-38971 -
Displacement parametersBiso mean: 52.8 Å2
Refinement stepCycle: LAST / Resolution: 2.7→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5390 0 97 18 5505
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_bond_d0.007

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