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Entry
Database: PDB / ID: 3wym
TitleCrystal structure of the catalytic domain of PDE10A complexed with 1-(2-fluoro-4-(1H-pyrazol-1-yl)phenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE 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 / 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-3K9 / 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 Å
AuthorsOki, H. / Hayano, Y.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063), a highly potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor.
Authors: Kunitomo, J. / Yoshikawa, M. / Fushimi, M. / Kawada, A. / Quinn, J.F. / Oki, H. / Kokubo, H. / Kondo, M. / Nakashima, K. / Kamiguchi, N. / Suzuki, K. / Kimura, H. / Taniguchi, T.
History
DepositionSep 1, 2014Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 19, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.2Dec 25, 2019Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.3Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_site
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_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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_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)78,8158
Polymers77,7792
Non-polymers1,0366
Water8,377465
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4084
Polymers38,8901
Non-polymers5183
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4084
Polymers38,8901
Non-polymers5183
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.701, 81.707, 161.533
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 38889.586 Da / Num. of mol.: 2 / Fragment: Catalytic domain, UNP residues 442-779
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta2 (DE3) pLysS
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-3K9 / 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one


Mass: 428.418 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H17FN6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 465 / 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: 2.11 Å3/Da / Density % sol: 41.66 % / Mosaicity: 0.816 °
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 200mM magnesium chloride hexahydrate, 25.7% PEG3350, vapor diffusion, hanging drop, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.97 Å
DetectorDetector: CCD / Date: Jul 18, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 45004 / % possible obs: 99.3 % / Redundancy: 5.6 % / Rmerge(I) obs: 0.111 / Χ2: 1.005 / Net I/σ(I): 8
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allRpim(I) allΧ2% possible allRrim(I) all
2-2.035.50.91722140.4220.942100
2.03-2.075.60.78522500.3590.9971000.865
2.07-2.115.60.66122060.3020.9931000.728
2.11-2.155.60.57522530.2620.9971000.634
2.15-2.25.60.4621880.211.0021000.507
2.2-2.255.60.43122640.1961.09499.90.474
2.25-2.315.60.37222010.171.01799.90.41
2.31-2.375.60.30922590.1411.01699.90.34
2.37-2.445.60.28822250.1311.00499.80.318
2.44-2.525.60.23822500.1081.00599.80.262
2.52-2.615.60.20722400.0940.99999.70.228
2.61-2.715.60.17722360.0811.01499.70.195
2.71-2.845.60.14422380.066199.30.159
2.84-2.995.60.11822450.0541.00799.60.13
2.99-3.175.60.09222580.0420.99999.10.102
3.17-3.425.60.07522470.0340.98498.90.083
3.42-3.765.50.07222640.0331.01898.70.08
3.76-4.315.40.06222640.0291.02598.10.069
4.31-5.435.40.04622970.0210.9998.20.05
5.43-505.40.03224050.0150.98696.70.035

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMACrefmac_5.8.0049refinement
PDB_EXTRACT3.15data extraction
HKL-2000data collection
DENZOdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→44.96 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.942 / WRfactor Rfree: 0.208 / WRfactor Rwork: 0.17 / SU B: 8.638 / SU ML: 0.122 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.193 / ESU R Free: 0.159 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2147 2196 4.9 %RANDOM
Rwork0.1788 ---
obs0.1805 42757 99.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 78.87 Å2 / Biso mean: 31.022 Å2 / Biso min: 12.78 Å2
Baniso -1Baniso -2Baniso -3
1-0.95 Å2-0 Å20 Å2
2---1.07 Å20 Å2
3---0.12 Å2
Refinement stepCycle: LAST / Resolution: 2→44.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5120 0 68 465 5653
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0195320
X-RAY DIFFRACTIONr_angle_refined_deg1.1721.9627208
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8245628
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.05924.08250
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.89115932
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7581528
X-RAY DIFFRACTIONr_chiral_restr0.0820.2778
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214144
X-RAY DIFFRACTIONr_mcbond_it1.0272.4152518
X-RAY DIFFRACTIONr_mcangle_it1.723.6133144
X-RAY DIFFRACTIONr_scbond_it1.4422.5862802
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.002-2.0540.2951760.2553089327799.634
2.054-2.110.2491530.23330773230100
2.11-2.1710.2881690.2192954312499.968
2.171-2.2380.251450.2062889303599.967
2.238-2.3110.2591200.1972803292599.932
2.311-2.3920.2681320.1922728286299.93
2.392-2.4830.221360.1862632277699.712
2.483-2.5840.2181200.1872536266299.775
2.584-2.6990.2071310.1812399253599.803
2.699-2.830.2341220.1872325246299.391
2.83-2.9830.225970.22230233699.615
2.983-3.1640.2611020.1942089221199.095
3.164-3.3820.194910.171986209099.378
3.382-3.6520.2061080.1751806194098.66
3.652-40.1871020.1531670180398.281
4-4.4710.177970.1441532165698.37
4.471-5.160.182620.1471370146397.881
5.16-6.3130.195630.1761173126497.785
6.313-8.9010.185410.14692599097.576
8.901-80.7670.139290.13954460694.554
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.3568-0.06620.04730.5022-0.11660.4232-0.04860.0427-0.02050.082-0.0065-0.0509-0.07280.0020.05510.0465-0.0025-0.01820.00760.00140.027316.50112.3953-13.1217
20.1290.0099-0.11540.7799-0.25340.78940.0196-0.00120.0381-0.0422-0.0798-0.04420.1111-0.01180.06020.05950.00030.01520.0111-0.00110.0267.3791-34.4269-26.4108
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A445 - 759
2X-RAY DIFFRACTION1A1001 - 1003
3X-RAY DIFFRACTION2B445 - 759
4X-RAY DIFFRACTION2B1001 - 1003

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