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- PDB-4g2j: Human pde9 in complex with selective compound -

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Basic information

Entry
Database: PDB / ID: 4g2j
TitleHuman pde9 in complex with selective compound
ComponentsHigh affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / phosphodiesterase / inhibitors / cGMP->GMP / 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-0WF / High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.4 Å
AuthorsLiu, S.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitors.
Authors: Claffey, M.M. / Helal, C.J. / Verhoest, P.R. / Kang, Z. / Fors, K.S. / Jung, S. / Zhong, J. / Bundesmann, M.W. / Hou, X. / Lui, S. / Kleiman, R.J. / Vanase-Frawley, M. / Schmidt, A.W. / ...Authors: Claffey, M.M. / Helal, C.J. / Verhoest, P.R. / Kang, Z. / Fors, K.S. / Jung, S. / Zhong, J. / Bundesmann, M.W. / Hou, X. / Lui, S. / Kleiman, R.J. / Vanase-Frawley, M. / Schmidt, A.W. / Menniti, F. / Schmidt, C.J. / Hoffman, W.E. / Hajos, M. / McDowell, L. / O'Connor, R.E. / Macdougall-Murphy, M. / Fonseca, K.R. / Becker, S.L. / Nelson, F.R. / Liras, S.
History
DepositionJul 12, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 29, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 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_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

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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)78,6648
Polymers77,7262
Non-polymers9386
Water6,612367
1
A: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,3324
Polymers38,8631
Non-polymers4693
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,3324
Polymers38,8631
Non-polymers4693
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
A: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)78,6648
Polymers77,7262
Non-polymers9386
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_645-y+3/2,x-1/2,z+1/41
Buried area2840 Å2
ΔGint-111 kcal/mol
Surface area28230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.688, 103.688, 270.075
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: UNP Residues 242-566
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE9A
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-0WF / 1-cyclopentyl-6-[(1R)-1-(3-phenoxyazetidin-1-yl)ethyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one


Mass: 379.456 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H25N5O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 367 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 4.67 Å3/Da / Density % sol: 73.66 %

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. all: 58708 / Num. obs: 58649 / % possible obs: 99.9 % / Observed criterion σ(I): 2 / Redundancy: 6.3 % / Biso Wilson estimate: 50.37 Å2 / Rmerge(I) obs: 0.117
Reflection shellResolution: 2.4→2.44 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.888 / Mean I/σ(I) obs: 2 / Num. unique all: 2884 / % possible all: 99.9

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Processing

SoftwareName: BUSTER / Version: 2.11.2 / Classification: refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.4→38.36 Å / Cor.coef. Fo:Fc: 0.9397 / Cor.coef. Fo:Fc free: 0.9361 / SU R Cruickshank DPI: 0.196 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2127 5948 10.17 %RANDOM
Rwork0.2005 ---
obs0.2018 58493 99.92 %-
Displacement parametersBiso mean: 44.12 Å2
Baniso -1Baniso -2Baniso -3
1--1.7919 Å20 Å20 Å2
2---1.7919 Å20 Å2
3---3.5837 Å2
Refine analyzeLuzzati coordinate error obs: 0.335 Å
Refinement stepCycle: LAST / Resolution: 2.4→38.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5412 0 60 367 5839
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0085666HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.987728HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1994SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes152HARMONIC2
X-RAY DIFFRACTIONt_gen_planes840HARMONIC5
X-RAY DIFFRACTIONt_it5666HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.25
X-RAY DIFFRACTIONt_other_torsion17.87
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion718SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact6903SEMIHARMONIC4
LS refinement shellResolution: 2.4→2.46 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2437 402 9.49 %
Rwork0.2323 3834 -
all0.2334 4236 -
obs--99.92 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.8879-0.48660.04140.9503-0.01491.24050.0898-0.05830.0190.0154-0.0110.0905-0.1286-0.0365-0.07880.0736-0.008-0.0032-0.10950.0031-0.113984.35945.66645.721
20.7468-0.19910.27751.4579-0.38811.79070.04340.1371-0.0931-0.0688-0.0267-0.03240.20240.128-0.01670.02920.04650.0140.0012-0.0243-0.087692.77531.8557.061
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|181 - A|505 }A181 - 505
2X-RAY DIFFRACTION2{ B|181 - B|505 }B181 - 505

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