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- PDB-4p1r: Crystal Structure of PDE10A with Imidazo[4,5-b]pyridines as Poten... -

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Basic information

Entry
Database: PDB / ID: 4p1r
TitleCrystal Structure of PDE10A with Imidazo[4,5-b]pyridines as Potent and Selective Inhibitors
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INBHITOR / HYDROLASE-HYDROLASE INHIBITOR COMPLEX / HYDROLASE-HYDROLASE INBHITOR 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-2KR / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.243 Å
AuthorsChmait, S.
CitationJournal: Acs Med.Chem.Lett. / Year: 2014
Title: Discovery of Novel Imidazo[4,5-b]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A).
Authors: Hu, E. / Andrews, K. / Chmait, S. / Zhao, X. / Davis, C. / Miller, S. / Hill Della Puppa, G. / Dovlatyan, M. / Chen, H. / Lester-Zeiner, D. / Able, J. / Biorn, C. / Ma, J. / Shi, J. / Treanor, J. / Allen, J.R.
History
DepositionFeb 27, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 23, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_src_gen / pdbx_database_status / pdbx_prerelease_seq / pdbx_struct_assembly / pdbx_struct_conn_angle / pdbx_struct_oper_list / refine_hist / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _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)81,93842
Polymers77,7792
Non-polymers4,15940
Water12,448691
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules

A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules

A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,89563
Polymers116,6693
Non-polymers6,22660
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation20_544-z,x-1/2,-y-1/21
crystal symmetry operation47_545y+1/2,-z-1/2,-x1
Buried area8400 Å2
ΔGint-275 kcal/mol
Surface area40510 Å2
MethodPISA
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules

B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules

B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,91963
Polymers116,6693
Non-polymers6,25060
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555z,x,y1
crystal symmetry operation9_555y,z,x1
Buried area6570 Å2
ΔGint-270 kcal/mol
Surface area38950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)252.971, 252.971, 252.971
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number196
Space group name H-MF23
Components on special symmetry positions
IDModelComponents
11B-815-

SO4

21B-815-

SO4

31A-1142-

HOH

41A-1154-

HOH

51A-1162-

HOH

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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: 38889.586 Da / Num. of mol.: 2 / Fragment: UNP residues 442-779
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

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Non-polymers , 5 types, 731 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#3: Chemical...
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 26 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-2KR / N-[4-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-5-methylpyridin-2-amine


Mass: 331.371 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H17N5O
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 691 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 4.34 Å3/Da / Density % sol: 71.63 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 1.6M Ammonium Sulfate, 0.1M MES monohydrate, 10% v/v 1,4-Dioxane

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jun 14, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5 Å / Relative weight: 1
ReflectionResolution: 2.24→29.81 Å / Num. obs: 63795 / % possible obs: 99.9 % / Redundancy: 4 % / Net I/σ(I): 12.39

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Processing

SoftwareName: PHENIX / Version: (phenix.refine: dev_1589) / Classification: refinement
RefinementResolution: 2.243→29.81 Å / SU ML: 0.18 / σ(F): 0 / Phase error: 17.95 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1888 3169 4.97 %
Rwork0.1527 --
obs0.1545 63577 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.243→29.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5081 0 232 691 6004
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0095420
X-RAY DIFFRACTIONf_angle_d1.3077346
X-RAY DIFFRACTIONf_dihedral_angle_d12.3751968
X-RAY DIFFRACTIONf_chiral_restr0.06777
X-RAY DIFFRACTIONf_plane_restr0.01907
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.243-2.27680.17131490.14262603X-RAY DIFFRACTION100
2.2768-2.31240.18671280.13462665X-RAY DIFFRACTION100
2.3124-2.35030.19431430.13622601X-RAY DIFFRACTION100
2.3503-2.39080.18491490.14012594X-RAY DIFFRACTION100
2.3908-2.43420.20151600.14312614X-RAY DIFFRACTION100
2.4342-2.4810.18481270.14612631X-RAY DIFFRACTION100
2.481-2.53170.18551050.14612672X-RAY DIFFRACTION100
2.5317-2.58670.22941240.15792609X-RAY DIFFRACTION100
2.5867-2.64680.18461410.15442623X-RAY DIFFRACTION100
2.6468-2.7130.19141490.16132625X-RAY DIFFRACTION100
2.713-2.78630.20011670.15582579X-RAY DIFFRACTION100
2.7863-2.86820.1741310.16022646X-RAY DIFFRACTION100
2.8682-2.96070.20591410.16932610X-RAY DIFFRACTION100
2.9607-3.06640.23081270.17152627X-RAY DIFFRACTION100
3.0664-3.1890.23481190.17162664X-RAY DIFFRACTION100
3.189-3.3340.20851530.17292639X-RAY DIFFRACTION100
3.334-3.50950.20461540.16342624X-RAY DIFFRACTION100
3.5095-3.7290.17531400.14682643X-RAY DIFFRACTION100
3.729-4.01630.16811380.14032630X-RAY DIFFRACTION100
4.0163-4.41930.15751240.13292642X-RAY DIFFRACTION100
4.4193-5.05610.15221320.13352685X-RAY DIFFRACTION100
5.0561-6.360.20961160.16772690X-RAY DIFFRACTION100
6.36-29.81550.18971520.15992710X-RAY DIFFRACTION99

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