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Entry
Database: PDB / ID: 4dff
TitleThe SAR development of dihydroimidazoisoquinoline derivatives as phosphodiesterase 10A inhibitors for the treatment of schizophrenia
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Zn binding / Mg binding / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process / cGMP effects / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity ...3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process / cGMP effects / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / cAMP-mediated signaling / G alpha (s) signalling events / 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 / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-0JP / 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. / Seganish, W.M. / Bercovici, A. / Tulshian, D. / Greenlee, W.J. / Van Rijn, R. / Hruza, A. / Xiao, L. / Rindgen, D. / Mullins, D. ...Ho, G.D. / Seganish, W.M. / Bercovici, A. / Tulshian, D. / Greenlee, W.J. / Van Rijn, R. / Hruza, A. / Xiao, L. / Rindgen, D. / Mullins, D. / Guzzi, M. / Zhang, X. / Bleichardt, C. / Hodgson, R.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: The SAR development of dihydroimidazoisoquinoline derivatives as phosphodiesterase 10A inhibitors for the treatment of schizophrenia.
Authors: Ho, G.D. / Michael Seganish, W. / Bercovici, A. / Tulshian, D. / Greenlee, W.J. / Van Rijn, R. / Hruza, A. / Xiao, L. / Rindgen, D. / Mullins, D. / Guzzi, M. / Zhang, X. / Bleickardt, C. / Hodgson, R.
History
DepositionJan 23, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 14, 2012Provider: repository / Type: Initial release
Revision 1.1Apr 4, 2012Group: Database references
Revision 1.2Oct 30, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / 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)81,4887
Polymers80,9952
Non-polymers4935
Water95553
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,5873
Polymers40,4971
Non-polymers902
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)40,9014
Polymers40,4971
Non-polymers4033
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.654, 81.177, 153.323
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 40497.473 Da / Num. of mol.: 2 / Fragment: catalytic domain (UNP residues 432-779)
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
#2: Chemical ChemComp-MG / MAGNESIUM ION


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


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-0JP / 8,9-dimethoxy-1-(1,3-thiazol-5-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline


Mass: 313.374 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H15N3O2S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 53 / 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: 1.87 Å3/Da / Density % sol: 34.19 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 100 mM HEPES, 16% PEG3350, 25 mM magnesium chloride, pH 7.4, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jun 30, 2008
RadiationMonochromator: Diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.1→30 Å / Num. all: 35208 / Num. obs: 31791 / % possible obs: 90.4 % / Observed criterion σ(I): 2.3 / Redundancy: 4 % / Biso Wilson estimate: 39.17 Å2 / Rsym value: 0.06 / Net I/σ(I): 17.2
Reflection shellResolution: 2.1→2.14 Å / Redundancy: 2 % / Rmerge(I) obs: 0.317 / Mean I/σ(I) obs: 2.3 / Num. unique all: 1222 / Rsym value: 0.317 / % possible all: 70.3

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.11→13.33 Å / Cor.coef. Fo:Fc: 0.9355 / Cor.coef. Fo:Fc free: 0.9285 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.253 / SU Rfree Blow DPI: 0.186 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2229 1615 5.09 %RANDOM
Rwork0.1899 ---
obs0.1916 31703 88.94 %-
Displacement parametersBiso mean: 67.42 Å2
Baniso -1Baniso -2Baniso -3
1--7.6087 Å20 Å20 Å2
2--11.6411 Å20 Å2
3----4.0324 Å2
Refine analyzeLuzzati coordinate error obs: 0.365 Å
Refinement stepCycle: LAST / Resolution: 2.11→13.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4736 0 26 53 4815
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2072SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes119HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1406HARMONIC5
X-RAY DIFFRACTIONt_it9551HARMONIC20
X-RAY DIFFRACTIONt_nbd7SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion630SEMIHARMONIC5
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_contact10130SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9551HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg17221HARMONIC20.97
X-RAY DIFFRACTIONt_omega_torsion2.97
X-RAY DIFFRACTIONt_other_torsion16.04
LS refinement shellResolution: 2.11→2.18 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.2391 100 5.35 %
Rwork0.2069 1768 -
all0.2087 1868 -
obs--88.94 %
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)
10.97480.4917-0.26671.8292-0.79133.83580.03320.0462-0.0243-0.24770.0160.05430.6582-0.1317-0.04920.09660.0064-0.0943-0.25510.0148-0.14836.84896.643851.2125
22.33570.84351.70242.35640.50182.1422-0.24920.11210.20760.14320.07930.0588-0.37590.0720.16990.08150.0368-0.0209-0.22010.0232-0.146417.92842.139964.8092
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A463 - 769
2X-RAY DIFFRACTION2{ B|* }B471 - 769

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