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- PDB-6kdz: Crystal structure of PDE10A in complex with a triazolopyrimidine ... -

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Basic information

Entry
Database: PDB / ID: 6kdz
TitleCrystal structure of PDE10A in complex with a triazolopyrimidine inhibitor
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE / Inhibitor
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 / 3',5'-cyclic-GMP phosphodiesterase activity / cGMP binding / 3',5'-cyclic-nucleotide 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 / 3',5'-cyclic-GMP phosphodiesterase activity / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / G alpha (s) signalling events / signal transduction / metal ion binding / cytosol
Similarity search - Function
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / GAF domain / 3'5'-cyclic nucleotide phosphodiesterase / Domain present in phytochromes and cGMP-specific phosphodiesterases. / 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. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / GAF domain / 3'5'-cyclic nucleotide phosphodiesterase / Domain present in phytochromes and cGMP-specific phosphodiesterases. / 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 / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-D79 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsAmano, Y. / Honbou, K.
CitationJournal: Bioorg.Med.Chem. / Year: 2019
Title: Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors.
Authors: Chino, A. / Honda, S. / Morita, M. / Yonezawa, K. / Hamaguchi, W. / Amano, Y. / Moriguchi, H. / Yamazaki, M. / Aota, M. / Tomishima, M. / Masuda, N.
History
DepositionJul 3, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 14, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 22, 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 / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_label_atom_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:
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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)79,7537
Polymers79,2132
Non-polymers5405
Water0
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0574
Polymers39,6061
Non-polymers4503
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,6963
Polymers39,6061
Non-polymers902
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)50.218, 81.044, 162.136
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.149184, -0.947423, -0.283078), (0.9801, -0.103768, -0.16922), (0.130948, -0.30269, 0.944051)59.19313, -7.18771, 24.13648

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Components

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


Mass: 39606.430 Da / Num. of mol.: 2
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
#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-D79 / 4-[2-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)ethyl]-3,7,8,10-tetrazatricyclo[7.4.0.0^{2,7}]trideca-1,3,5,8,10,12-hexaen-6-ol


Mass: 360.373 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H16N8O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: 2.2 Å3/Da / Density % sol: 43.99 %
Crystal growTemperature: 296 K / Method: vapor diffusion, sitting drop
Details: 50mM Bis-tris propane pH6.0, 50mM Magnesium sulfate, 15% PEG 3350

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Data collection

DiffractionMean temperature: 95 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS VII / Detector: IMAGE PLATE / Date: Sep 12, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 3.1→47.97 Å / Num. obs: 11416 / % possible obs: 90.6 % / Redundancy: 2.91 % / Rmerge(I) obs: 0.141 / Rrim(I) all: 0.141 / Χ2: 0.97 / Net I/σ(I): 5.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsΧ2% possible allRejects
3.1-3.213.040.5091.8317310431.0285.4
3.21-3.343.010.4851.832201071186.4
3.34-3.493.010.4042.2319410601.0386.3
3.49-3.682.940.2983.1324811051.0188.32
3.68-3.912.930.2433.9322811021.0488.93
3.91-4.212.860.1984.3321511250.9290.33
4.21-4.632.850.145.9338611870.8994.73
4.63-5.32.840.1126.9347012200.8896.13
5.3-6.672.940.1157.2366712490.8697.61
6.67-47.952.740.04115.836691254191.2237

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Processing

Software
NameVersionClassification
d*TREK9.4SSIdata scaling
REFMAC5.6.0117refinement
PDB_EXTRACT3.25data extraction
CrystalCleardata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OUN

2oun


Resolution: 3.1→47.97 Å / Cor.coef. Fo:Fc: 0.903 / Cor.coef. Fo:Fc free: 0.827 / SU B: 31.997 / SU ML: 0.551 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.742 / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.3252 550 4.8 %RANDOM
Rwork0.2525 ---
obs0.256 10821 90.15 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 154.52 Å2 / Biso mean: 72.896 Å2 / Biso min: 34.85 Å2
Baniso -1Baniso -2Baniso -3
1--0.33 Å20 Å20 Å2
2---0.33 Å20 Å2
3---0.66 Å2
Refinement stepCycle: final / Resolution: 3.1→47.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5258 0 31 0 5289
Biso mean--56.09 --
Num. residues----648
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.025419
X-RAY DIFFRACTIONr_angle_refined_deg1.541.9537340
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8955646
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.42124.141256
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.2115960
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.1861528
X-RAY DIFFRACTIONr_chiral_restr0.1020.2800
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214130
LS refinement shellResolution: 3.1→3.18 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.377 33 -
Rwork0.305 660 -
all-693 -
obs--82.5 %

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