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Basic information

Entry
Database: PDB / ID: 3uuo
TitleThe discovery of potent, selectivity, and orally bioavailable pyrozoloquinolines as PDE10 inhibitors for the treatment of Schizophrenia
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / INHIBITOR COMPLEX / HYDROLASE / ZN BINDING / MG BINDING / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


extrinsic component of postsynaptic density membrane / 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cGMP-inhibited cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process / cAMP catabolic process / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding ...extrinsic component of postsynaptic density membrane / 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cGMP-inhibited cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process / cAMP catabolic process / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP-mediated signaling / cAMP binding / G alpha (s) signalling events / perikaryon / glutamatergic synapse / metal ion binding / 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. / GAF domain ...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. / GAF domain / Domain present in phytochromes and cGMP-specific phosphodiesterases. / GAF domain / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / GAF-like domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-0CV / PHOSPHATE ION / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.11 Å
AuthorsHo, G.D. / Yang, S. / Smotryski, J. / Bercovici, A. / Nechuta, T. / Smith, E.M. / McElroy, W. / Tan, Z. / Tulshian, D. / Mckittrick, B. ...Ho, G.D. / Yang, S. / Smotryski, J. / Bercovici, A. / Nechuta, T. / Smith, E.M. / McElroy, W. / Tan, Z. / Tulshian, D. / Mckittrick, B. / Greenlee, W.J. / Hruza, A. / Xiao, L. / Rindgen, D. / Guzzi, M. / Zhang, X. / Bleickardt, C. / Mullins, D. / Hodgson, R.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: The discovery of potent, selective, and orally active pyrazoloquinolines as PDE10A inhibitors for the treatment of Schizophrenia.
Authors: Ho, G.D. / Yang, S.W. / Smotryski, J. / Bercovici, A. / Nechuta, T. / Smith, E.M. / McElroy, W. / Tan, Z. / Tulshian, D. / McKittrick, B. / Greenlee, W.J. / Hruza, A. / Xiao, L. / Rindgen, D. ...Authors: Ho, G.D. / Yang, S.W. / Smotryski, J. / Bercovici, A. / Nechuta, T. / Smith, E.M. / McElroy, W. / Tan, Z. / Tulshian, D. / McKittrick, B. / Greenlee, W.J. / Hruza, A. / Xiao, L. / Rindgen, D. / Mullins, D. / Guzzi, M. / Zhang, X. / Bleickardt, C. / Hodgson, R.
History
DepositionNov 28, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2012Provider: 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: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,00810
Polymers78,0162
Non-polymers9928
Water1,910106
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,5045
Polymers39,0081
Non-polymers4964
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,5045
Polymers39,0081
Non-polymers4964
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.566, 82.231, 161.340
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A


Mass: 39007.914 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN, UNP residues 432-760
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase

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Non-polymers , 5 types, 114 molecules

#2: Chemical ChemComp-0CV / 6-methoxy-3,8-dimethyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]quinoline


Mass: 311.382 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H21N5O
#3: Chemical ChemComp-MG / MAGNESIUM ION


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


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 106 / 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: 2.15 Å3/Da / Density % sol: 42.78 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 100MM HEPES, 16% PEG 3350, 25 MM MGCL2, pH 7.4, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 0.9777 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jul 2, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9777 Å / Relative weight: 1
ReflectionResolution: 2.1→30 Å / Num. all: 39884 / Num. obs: 37616 / % possible obs: 94.4 % / Observed criterion σ(I): 2 / Biso Wilson estimate: 32.99 Å2 / Rmerge(I) obs: 0.077
Reflection shellResolution: 2.1→2.18 Å / % possible all: 73.3

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Processing

Software
NameVersionClassification
StructureStudiodata collection
BUSTER2.11.2refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.11→29.79 Å / Cor.coef. Fo:Fc: 0.9322 / Cor.coef. Fo:Fc free: 0.9113 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
Details: Refined with hydrogen added by programs Molprobity and Affit
RfactorNum. reflection% reflectionSelection details
Rfree0.2267 1874 5.03 %RANDOM
Rwork0.1949 ---
obs0.1965 37288 94.25 %-
Displacement parametersBiso mean: 52.28 Å2
Baniso -1Baniso -2Baniso -3
1--8.938 Å20 Å20 Å2
2--14.7193 Å20 Å2
3----5.7813 Å2
Refine analyzeLuzzati coordinate error obs: 0.309 Å
Refinement stepCycle: LAST / Resolution: 2.11→29.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5033 0 60 106 5199
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00910237HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9418477HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2210SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes127HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1499HARMONIC5
X-RAY DIFFRACTIONt_it10237HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.76
X-RAY DIFFRACTIONt_other_torsion16.66
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion666SEMIHARMONIC5
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_contact10018SEMIHARMONIC4
LS refinement shellResolution: 2.11→2.17 Å / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.2433 104 4.73 %
Rwork0.2172 2097 -
all0.2185 2201 -
obs--94.25 %
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)
10.67890.0911-0.20712.3736-0.00662.14920.03910.05230.05160.1202-0.1086-0.12910.2099-0.0510.0695-0.0613-0.0176-0.0285-0.09280.0163-0.17247.30715.855553.3431
20.83940.0040.31222.0094-0.04851.3852-0.03930.01730.0050.2085-0.0481-0.2825-0.18610.00640.0874-0.0388-0.0033-0.0742-0.09340.0179-0.105917.937243.327267.3606
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A465 - 769
2X-RAY DIFFRACTION2{ B|* }B455 - 769

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