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- PDB-5axp: Crystal structure of the catalytic domain of PDE10A complexed wit... -

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Basic information

Entry
Database: PDB / ID: 5axp
TitleCrystal structure of the catalytic domain of PDE10A complexed with 1-(2-fluoro-4-(2-oxo-1,3-oxazolidin-3-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-nucleotide phosphodiesterase activity / cGMP binding / 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 / 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 / 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-4LK / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsOki, H. / Zama, Y.
CitationJournal: Bioorg.Med.Chem. / Year: 2015
Title: Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor
Authors: Yoshikawa, M. / Kamisaki, H. / Kunitomo, J. / Oki, H. / Kokubo, H. / Suzuki, A. / Ikemoto, T. / Nakashima, K. / Kamiguchi, N. / Harada, A. / Kimura, H. / Taniguchi, T.
History
DepositionJul 31, 2015Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 11, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 18, 2015Group: Database references
Revision 1.2Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_struct_conn_angle / pdbx_struct_oper_list / struct_conn
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _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 / _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

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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)78,8538
Polymers77,7792
Non-polymers1,0746
Water5,639313
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4274
Polymers38,8901
Non-polymers5373
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-34 kcal/mol
Surface area14500 Å2
MethodPISA
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4274
Polymers38,8901
Non-polymers5373
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-33 kcal/mol
Surface area14340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.753, 81.849, 159.684
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-4LK / 3-[3-fluoranyl-4-[5-methoxy-4-oxidanylidene-3-(2-phenylpyrazol-3-yl)pyridazin-1-yl]phenyl]-1,3-oxazolidin-2-one


Mass: 447.419 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H18FN5O4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 313 / 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: 2.22 Å3/Da / Density % sol: 44.71 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 8
Details: 100 mM HEPES pH 8.0, 100 mM mM magnesium chloride hexahydrate, 25.7% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.97645 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 24, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97645 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. obs: 45993 / % possible obs: 95 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.032 / Rrim(I) all: 0.084 / Χ2: 1.008 / Net I/av σ(I): 19.574 / Net I/σ(I): 13.2 / Num. measured all: 296940
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.95-1.9830.54913910.750.30.6320.9658.6
1.98-2.023.50.52316390.8070.2780.5980.98169.9
2.02-2.063.90.43919510.8650.2250.4971.00680.8
2.06-2.14.60.42122030.8870.2060.4721.04292.4
2.1-2.155.50.36823280.9340.1660.4051.01696.9
2.15-2.26.30.30223360.9640.1280.3290.98199.4
2.2-2.256.70.30924010.9670.1280.3361.06199.9
2.25-2.317.10.26323830.9830.1060.2841.025100
2.31-2.387.30.22924290.9860.0910.2470.988100
2.38-2.467.30.20323870.9890.080.2181.017100
2.46-2.547.30.16623980.9920.0660.1781.006100
2.54-2.657.30.13924080.9940.0550.1491.013100
2.65-2.777.30.12124120.9940.0480.131.004100
2.77-2.917.30.09624270.9960.0380.1031.008100
2.91-3.17.20.08224130.9970.0320.0881.001100
3.1-3.337.20.06724400.9980.0270.0721.014100
3.33-3.677.10.05624390.9980.0220.0610.999100
3.67-4.26.80.05624590.9970.0230.060.98999.8
4.2-5.296.70.05225040.9970.0220.0570.99999.9
5.29-506.40.0526450.9970.0220.0550.99899.8

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMACrefmac_5.8.0049refinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→50 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.941 / Matrix type: sparse / WRfactor Rfree: 0.236 / WRfactor Rwork: 0.18 / SU B: 9.06 / SU ML: 0.126 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.179 / ESU R Free: 0.167 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2335 2242 4.9 %RANDOM
Rwork0.1757 43643 --
obs0.1785 43643 94.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 128.95 Å2 / Biso mean: 38.899 Å2 / Biso min: 18.92 Å2
Baniso -1Baniso -2Baniso -3
1-2.94 Å2-0 Å20 Å2
2---3.42 Å20 Å2
3---0.48 Å2
Refinement stepCycle: final / Resolution: 1.95→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5120 0 70 313 5503
Biso mean--31.85 41.04 -
Num. residues----630
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0195326
X-RAY DIFFRACTIONr_angle_refined_deg1.211.9637219
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8465630
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.61424.08250
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.77415933
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.561528
X-RAY DIFFRACTIONr_chiral_restr0.0820.2779
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214144
X-RAY DIFFRACTIONr_mcbond_it2.8383.8222520
X-RAY DIFFRACTIONr_mcangle_it3.6736.4173147
X-RAY DIFFRACTIONr_scbond_it5.1474.4332806
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 (%)WRfactor Rwork
1.95-20.3271110.2651944354957.9040.231
2-2.0550.2361250.2342495340277.0140.198
2.055-2.1150.2751190.2343012336593.0460.202
2.115-2.180.2421420.2113084327998.3840.183
2.18-2.2510.2621540.2042995315199.9370.181
2.251-2.330.2661460.1992914306199.9670.179
2.33-2.4180.261570.203279529521000.179
2.418-2.5160.2571370.1832724286399.930.166
2.516-2.6280.2431340.1882624276199.8910.172
2.628-2.7560.2471540.1832451260699.9620.17
2.756-2.9050.2781300.1932364250399.640.184
2.905-3.0810.2541230.1992232236099.7880.194
3.081-3.2940.2661120.182132224999.7780.184
3.294-3.5570.2231000.1741996210199.7620.184
3.557-3.8960.192910.1461823192399.5320.164
3.896-4.3540.19820.1421659174699.7140.17
4.354-5.0250.177760.1361502158299.7470.165
5.025-6.1490.274720.1621270134399.9260.194
6.149-8.670.153390.149102610651000.186
8.67-79.8420.229380.17160264699.0710.202
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)
10.2594-0.16850.13010.60610.03910.6113-0.0505-0.0008-0.02430.0181-0.0084-0.028-0.07680.03090.0590.01710.0035-0.00450.07590.00150.022915.9982.363-13.211
20.25750.4445-0.0771.2562-0.17380.5317-0.00670.03440.04450.0066-0.0181-0.0060.1388-0.01810.02480.05420.0004-0.00160.08310.01730.02577.004-34.564-26.139
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A442 - 1003
2X-RAY DIFFRACTION2B442 - 1002

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