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- PDB-4zo5: PDE10 complexed with 4-isopropoxy-2-(2-(3-(4-methoxyphenyl)-4-oxo... -

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Basic information

Entry
Database: PDB / ID: 4zo5
TitlePDE10 complexed with 4-isopropoxy-2-(2-(3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)isoindoline-1,3-dione
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Keywordshydrolase/hydrolase inhibitor / Phosphodiesterase inhibitor / hydrolase-hydrolase inhibitor complex
Function / homology
Function and homology information


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 / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity ...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 / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / 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 / GAF domain / 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. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 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. / 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-4PX / Chem-4Q0 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.5 Å
AuthorsYan, Y.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Discovery of [(11)C]MK-8193 as a PET tracer to measure target engagement of phosphodiesterase 10A (PDE10A) inhibitors.
Authors: Cox, C.D. / Hostetler, E.D. / Flores, B.A. / Evelhoch, J.L. / Fan, H. / Gantert, L. / Holahan, M. / Eng, W. / Joshi, A. / McGaughey, G. / Meng, X. / Purcell, M. / Raheem, I.T. / Riffel, K. / ...Authors: Cox, C.D. / Hostetler, E.D. / Flores, B.A. / Evelhoch, J.L. / Fan, H. / Gantert, L. / Holahan, M. / Eng, W. / Joshi, A. / McGaughey, G. / Meng, X. / Purcell, M. / Raheem, I.T. / Riffel, K. / Yan, Y. / Renger, J.J. / Smith, S.M. / Coleman, P.J.
History
DepositionMay 6, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 12, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 28, 2015Group: Database references
Revision 1.2Sep 27, 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 / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / pdbx_struct_oper_list / struct_conn
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _pdbx_struct_oper_list.symmetry_operation / _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

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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)75,8748
Polymers74,8602
Non-polymers1,0136
Water39622
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1280 Å2
ΔGint-107 kcal/mol
Surface area28390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.070, 81.380, 159.180
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 37430.156 Da / Num. of mol.: 2 / Fragment: catalytic domain, unp residues 449-769
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Production host: Escherichia coli (E. coli)
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase

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Non-polymers , 5 types, 28 molecules

#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-4PX / 3-(1-hydroxy-2-methylpropan-2-yl)-5-phenyl-3,5-dihydro-1H-imidazo[4,5-c][1,8]naphthyridine-2,4-dione


Mass: 350.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H18N4O3
#5: Chemical ChemComp-4Q0 / 2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-(propan-2-yloxy)-1H-isoindole-1,3(2H)-dione


Mass: 483.515 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H25N3O5
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 22 / 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: 2.21 Å3/Da / Density % sol: 44.33 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 100mM HEPES pH 7.0, 20% PEG3350, 200mM MgCl2, and 10mM 2-Mercaptoethanol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 8, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 21936 / % possible obs: 92 % / Redundancy: 5.6 % / Net I/σ(I): 21.1

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.15data extraction
DENZOdata reduction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2OUN

2oun


Resolution: 2.5→48.63 Å / Cor.coef. Fo:Fc: 0.9062 / Cor.coef. Fo:Fc free: 0.8757 / SU R Cruickshank DPI: 1.404 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.51 / SU Rfree Blow DPI: 0.352 / SU Rfree Cruickshank DPI: 0.356
RfactorNum. reflection% reflectionSelection details
Rfree0.285 1128 5.15 %RANDOM
Rwork0.2382 ---
obs0.2407 21890 91.14 %-
Displacement parametersBiso max: 149.56 Å2 / Biso mean: 71.55 Å2 / Biso min: 27.49 Å2
Baniso -1Baniso -2Baniso -3
1--27.477 Å20 Å20 Å2
2--19.6145 Å20 Å2
3---7.8625 Å2
Refine analyzeLuzzati coordinate error obs: 0.459 Å
Refinement stepCycle: final / Resolution: 2.5→48.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5139 0 66 22 5227
Biso mean--49.72 46.64 -
Num. residues----646
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1813SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes125HARMONIC8
X-RAY DIFFRACTIONt_gen_planes788HARMONIC8
X-RAY DIFFRACTIONt_it5337HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion693SEMIHARMONIC5
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_contact6314SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5337HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg7250HARMONIC21.13
X-RAY DIFFRACTIONt_omega_torsion1.82
X-RAY DIFFRACTIONt_other_torsion19.08
LS refinement shellResolution: 2.49→2.61 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.3147 118 5.49 %
Rwork0.2855 2031 -
all0.2869 2149 -
obs--91.14 %

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