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- PDB-3jsi: Human phosphodiesterase 9 in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 3jsi
TitleHuman phosphodiesterase 9 in complex with inhibitor
ComponentsHigh affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
KeywordsHYDROLASE / phosphodiesterase / inhibitor / Alternative splicing / cGMP / Manganese / Metal-binding / Phosphoprotein
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
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-WTC / High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.72 Å
AuthorsLiu, S.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Identification of a Brain Penetrant PDE9A Inhibitor Utilizing Prospective Design and Chemical Enablement as a Rapid Lead Optimization Strategy.
Authors: Verhoest, P.R. / Proulx-Lafrance, C. / Corman, M. / Chenard, L. / Helal, C.J. / Hou, X. / Kleiman, R. / Liu, S. / Marr, E. / Menniti, F.S. / Schmidt, C.J. / Vanase-Frawley, M. / Schmidt, A.W. ...Authors: Verhoest, P.R. / Proulx-Lafrance, C. / Corman, M. / Chenard, L. / Helal, C.J. / Hou, X. / Kleiman, R. / Liu, S. / Marr, E. / Menniti, F.S. / Schmidt, C.J. / Vanase-Frawley, M. / Schmidt, A.W. / Williams, R.D. / Nelson, F.R. / Fonseca, K.R. / Liras, S.
History
DepositionSep 10, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 1, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Sep 6, 2023Group: 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_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_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_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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)78,4948
Polymers77,7262
Non-polymers7686
Water52229
1
A: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,2474
Polymers38,8631
Non-polymers3843
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,2474
Polymers38,8631
Non-polymers3843
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)104.099, 104.099, 271.040
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: 38862.926 Da / Num. of mol.: 2 / Fragment: Catalytic domain: UNP residues 242-566
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE9A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
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-WTC / 6-benzyl-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one


Mass: 294.351 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H18N4O
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 29 / 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: 4.72 Å3/Da / Density % sol: 73.96 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: May 10, 2009 / Details: mirror
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. all: 26267 / Num. obs: 26056 / Observed criterion σ(I): 2 / Biso Wilson estimate: 42.65 Å2

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Processing

Software
NameVersionClassification
BUSTER2.9.2refinement
HKL-2000data reduction
HKL-2000data scaling
BUSTER2.9.2phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 3DYN

3dyn


Resolution: 2.72→43.65 Å / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2182 2715 10.42 %RANDOM
Rwork0.205 ---
obs0.205 26056 --
Displacement parametersBiso mean: 51.21 Å2
Baniso -1Baniso -2Baniso -3
1--7.7423 Å20 Å20 Å2
2---7.7423 Å20 Å2
3---15.4845 Å2
Refine analyzeLuzzati coordinate error obs: 0.453 Å
Refinement stepCycle: LAST / Resolution: 2.72→43.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5412 0 48 29 5489
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONo_bond_d0.008
X-RAY DIFFRACTIONo_bond_d_na
X-RAY DIFFRACTIONo_bond_d_prot
X-RAY DIFFRACTIONo_angle_d
X-RAY DIFFRACTIONo_angle_d_na
X-RAY DIFFRACTIONo_angle_d_prot
X-RAY DIFFRACTIONo_angle_deg0.97
X-RAY DIFFRACTIONo_angle_deg_na
X-RAY DIFFRACTIONo_angle_deg_prot
X-RAY DIFFRACTIONo_dihedral_angle_d
X-RAY DIFFRACTIONo_dihedral_angle_d_na
X-RAY DIFFRACTIONo_dihedral_angle_d_prot
X-RAY DIFFRACTIONo_improper_angle_d
X-RAY DIFFRACTIONo_improper_angle_d_na
X-RAY DIFFRACTIONo_improper_angle_d_prot
X-RAY DIFFRACTIONo_mcbond_it
X-RAY DIFFRACTIONo_mcangle_it
X-RAY DIFFRACTIONo_scbond_it
X-RAY DIFFRACTIONo_scangle_it
LS refinement shellResolution: 2.72→2.82 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.27 30 7 %
Rwork0.2297 1892 -

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