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- PDB-4bbx: Discovery of a potent, selective and orally active PDE10A inhibit... -

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Basic information

Entry
Database: PDB / ID: 4bbx
TitleDiscovery of a potent, selective and orally active PDE10A inhibitor for the treatment of schizophrenia
ComponentsCAMP AND CAMP-INHIBITED CGMP 3', 5'-CYCLIC PHOSPHODIESTERASE 10A
KeywordsHYDROLASE / PHOSPHODIESTERASE INHIBITOR / INHIBITOR COMPLEX / ZINC BINDING / MAGNESIUM BINDING
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-LKF / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsBartolome-Nebreda, J.M. / Conde-Ceide, S. / Delgado, F. / Martin, M.L. / Martinez-Viturro, C.M. / Pastor, J. / Tong, H.M. / Iturrino, L. / Macdonald, G.J. / Sanderson, W. ...Bartolome-Nebreda, J.M. / Conde-Ceide, S. / Delgado, F. / Martin, M.L. / Martinez-Viturro, C.M. / Pastor, J. / Tong, H.M. / Iturrino, L. / Macdonald, G.J. / Sanderson, W. / Megens, A. / Langlois, X. / Somers, M. / Vanhoof, G.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of a Potent, Selective and Orally Active Pde10A Inhibitor for the Potential Treatment of Schizophrenia.
Authors: Bartolome-Nebreda, J.M. / Delgado, F. / Martin, M.L. / Martinez-Viturro, C.M. / Pastor, J. / Tong, H.M. / Iturrino, L. / Macdonald, G.J. / Sanderson, W.E. / Megens, A. / Langlois, X. / ...Authors: Bartolome-Nebreda, J.M. / Delgado, F. / Martin, M.L. / Martinez-Viturro, C.M. / Pastor, J. / Tong, H.M. / Iturrino, L. / Macdonald, G.J. / Sanderson, W.E. / Megens, A. / Langlois, X. / Somers, M. / Vanhoof, G. / Conde Ceide, S.
History
DepositionSep 28, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 16, 2013Provider: repository / Type: Initial release
Revision 1.1May 7, 2014Group: Database references
Revision 1.2Jun 4, 2014Group: Database references

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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)78,8748
Polymers77,9822
Non-polymers8926
Water95553
1
A: CAMP AND CAMP-INHIBITED CGMP 3', 5'-CYCLIC PHOSPHODIESTERASE 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4374
Polymers38,9911
Non-polymers4463
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)39,4374
Polymers38,9911
Non-polymers4463
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.288, 81.283, 158.622
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 / PHOSPHODIESTERASE 10A


Mass: 38990.762 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN, RESIDUES 443-769
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Organ: BRAIN / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-LKF / 4-[3-[1-[(2S)-2-methoxypropyl]pyrazol-4-yl]-2-methyl-imidazo[1,2-a]pyrazin-8-yl]morpholine


Mass: 356.422 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H24N6O2
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 53 / 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 Å3/Da / Density % sol: 40 % / Description: NONE
Crystal growpH: 8.9
Details: 18% W/V PEG3350, 0.1 M TRIS-HCL PH 8.9, 5 MM CALCIUM CHLORIDE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54
DetectorType: RIGAKU IMAGE PLATE / Detector: IMAGE PLATE / Date: Apr 21, 2008 / Details: MIRROR
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.5→47.07 Å / Num. obs: 22069 / % possible obs: 96.5 % / Observed criterion σ(I): 2 / Redundancy: 2.9 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 7.2
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.42 / Mean I/σ(I) obs: 2.3 / % possible all: 94.5

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
CrystalCleardata reduction
CrystalCleardata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→79.31 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.905 / SU B: 16.194 / SU ML: 0.338 / Cross valid method: THROUGHOUT / ESU R: 2.179 / ESU R Free: 0.374 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.29344 1119 5.1 %RANDOM
Rwork0.23405 ---
obs0.23704 20916 96.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 47.504 Å2
Baniso -1Baniso -2Baniso -3
1-3.16 Å20 Å20 Å2
2---2.36 Å20 Å2
3----0.8 Å2
Refinement stepCycle: LAST / Resolution: 2.5→79.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5022 0 56 53 5131
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0225204
X-RAY DIFFRACTIONr_bond_other_d0.0010.023486
X-RAY DIFFRACTIONr_angle_refined_deg1.1381.9637058
X-RAY DIFFRACTIONr_angle_other_deg0.863.0018462
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7355622
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.79324.132242
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.23815894
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.7291526
X-RAY DIFFRACTIONr_chiral_restr0.0580.2774
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025718
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021048
X-RAY DIFFRACTIONr_nbd_refined0.2280.21425
X-RAY DIFFRACTIONr_nbd_other0.1770.23650
X-RAY DIFFRACTIONr_nbtor_refined0.1840.22612
X-RAY DIFFRACTIONr_nbtor_other0.0860.22544
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1680.2141
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined0.0950.28
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1980.215
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2080.251
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1870.22
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.4421.53387
X-RAY DIFFRACTIONr_mcbond_other0.0571.51250
X-RAY DIFFRACTIONr_mcangle_it0.75625042
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.71632336
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it1.0994.52016
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.5→2.565 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.419 88 -
Rwork0.35 1473 -
obs--94.15 %

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