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

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Basic information

Entry
Database: PDB / ID: 6kdx
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 / 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-D6X / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.44 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 / pdbx_struct_conn_angle / struct_conn
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_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)79,7117
Polymers79,2132
Non-polymers4985
Water36020
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0154
Polymers39,6061
Non-polymers4083
Water181
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
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)50.417, 81.440, 159.976
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(-0.156966, -0.944792, -0.287629), (0.980833, -0.115086, -0.157234), (0.115451, -0.306796, 0.944747)59.46973, -7.83904, 24.479219

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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-D6X / N-[2-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)ethyl]quinolin-2-amine


Mass: 318.376 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18N6 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 20 / Source method: isolated from a natural source / Formula: H2O
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: 2.19 Å3/Da / Density % sol: 43.73 %
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: SYNCHROTRON / Site: Photon Factory / Beamline: AR-NE3A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Jun 13, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.44→50 Å / Num. obs: 23193 / % possible obs: 91.2 % / Redundancy: 5.4 % / Rmerge(I) obs: 0.073 / Χ2: 2.357 / Net I/σ(I): 15.2 / Num. measured all: 125343
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.44-2.485.50.40111381.779191.4
2.48-2.535.50.33611371.818190
2.53-2.585.40.28511701.815194.8
2.58-2.635.40.2511671.846192.8
2.63-2.695.40.25511222.024191.3
2.69-2.755.40.20711791.89193.7
2.75-2.825.40.19311811.937192.3
2.82-2.895.50.15411471.903194
2.89-2.985.40.14611541.938191.4
2.98-3.075.50.11811542.052193.4
3.07-3.185.50.10711692.19192.3
3.18-3.315.50.08511722.213192.6
3.31-3.465.40.07411422.56191.7
3.46-3.645.40.06211682.566191
3.64-3.875.30.05811582.928190.6
3.87-4.175.30.05411552.962190.2
4.17-4.595.20.04711492.846189.3
4.59-5.255.50.04911802.915191.9
5.25-6.625.60.05212072.95191.1
6.62-504.90.05711444.247180.4

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.6.0117refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OUP

2oup


Resolution: 2.44→26.66 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.896 / SU B: 13.261 / SU ML: 0.297 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.673 / ESU R Free: 0.379 / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.3009 1187 5.1 %RANDOM
Rwork0.2414 ---
obs0.2444 21947 91.13 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 133.75 Å2 / Biso mean: 56.869 Å2 / Biso min: 27.06 Å2
Baniso -1Baniso -2Baniso -3
1-0.38 Å20 Å20 Å2
2---0.16 Å20 Å2
3----0.21 Å2
Refinement stepCycle: final / Resolution: 2.44→26.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5258 0 28 20 5306
Biso mean--38.66 36.82 -
Num. residues----648
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.025415
X-RAY DIFFRACTIONr_angle_refined_deg1.8231.9527332
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0385646
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.50224.141256
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.88515960
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.151528
X-RAY DIFFRACTIONr_chiral_restr0.1210.2800
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0214120
LS refinement shellResolution: 2.44→2.501 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.398 80 -
Rwork0.341 1439 -
obs--89.46 %

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