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- PDB-3wi2: Crystal structure of PDE10A in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 3wi2
TitleCrystal structure of PDE10A in complex with inhibitor
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / phosphodiesterase / cGMP 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-P98 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsAmano, Y.
CitationJournal: Bioorg.Med.Chem. / Year: 2013
Title: Design and synthesis of novel benzimidazole derivatives as phosphodiesterase 10A inhibitors with reduced CYP1A2 inhibition.
Authors: Hamaguchi, W. / Masuda, N. / Isomura, M. / Miyamoto, S. / Kikuchi, S. / Amano, Y. / Honbou, K. / Mihara, T. / Watanabe, T.
History
DepositionSep 4, 2013Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 11, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 24, 2022Group: Database references / Derived calculations
Category: citation / database_2 ...citation / database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _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
Revision 1.2May 29, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)80,1798
Polymers79,2132
Non-polymers9666
Water23413
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0904
Polymers39,6061
Non-polymers4833
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)40,0904
Polymers39,6061
Non-polymers4833
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.115, 81.629, 158.084
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: 39606.430 Da / Num. of mol.: 2 / Fragment: catalytic domain, UNP RESIDUES 439-779
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-P98 / 2-({[1-phenyl-2-(propan-2-yl)-1H-benzimidazol-6-yl]oxy}methyl)quinoline


Mass: 393.480 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H23N3O
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 13 / 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: 2.04 Å3/Da / Density % sol: 39.74 %
Crystal growTemperature: 296 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 50mM Bis-tris propane pH6.0, 50mM Magnesium sulfate, 15% PEG 3350, VAPOR DIFFUSION, SITTING DROP, temperature 296K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS VII / Detector: IMAGE PLATE / Date: Apr 2, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.26→19.96 Å / Num. obs: 30690

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Processing

Software
NameVersionClassification
CrystalCleardata collection
AMoREphasing
REFMAC5.7.0029refinement
CrystalCleardata reduction
CrystalCleardata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.26→19.96 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.889 / SU B: 12.401 / SU ML: 0.297 / Cross valid method: THROUGHOUT / ESU R: 0.488 / ESU R Free: 0.327 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.32913 1542 5 %RANDOM
Rwork0.25299 ---
obs0.25684 29030 97.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 56.247 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å20 Å20 Å2
2--0.01 Å2-0 Å2
3---0.01 Å2
Refinement stepCycle: LAST / Resolution: 2.26→19.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5258 0 64 13 5335
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0195456
X-RAY DIFFRACTIONr_angle_refined_deg1.7471.967390
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5165646
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.64324.141256
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.88615960
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.3571528
X-RAY DIFFRACTIONr_chiral_restr0.1110.2800
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0214222
LS refinement shellResolution: 2.26→2.318 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.531 121 -
Rwork0.435 2095 -
obs--99.95 %

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