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- PDB-3hqz: Discovery of novel inhibitors of PDE10A -

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Basic information

Entry
Database: PDB / ID: 3hqz
TitleDiscovery of novel inhibitors of PDE10A
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Phosphodiesterase 10A PDE 10A PDE10 inhibitors / Allosteric enzyme / Alternative splicing / cAMP / cAMP-binding / cGMP / cGMP-binding / Cytoplasm / Hydrolase / Magnesium / Metal-binding / Nucleotide-binding / Zinc / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / cyclic-nucleotide phosphodiesterase activity / cGMP effects / G alpha (s) signalling events / regulation of protein kinase A signaling / negative regulation of cAMP-mediated signaling / cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process ...regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / cyclic-nucleotide phosphodiesterase activity / cGMP effects / G alpha (s) signalling events / regulation of protein kinase A signaling / negative regulation of cAMP-mediated signaling / cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process / 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 / perikaryon / neuronal cell body / 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-PF8 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsPandit, J. / Marr, E.S.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Discovery of a Novel Class of Phosphodiesterase 10A Inhibitors and Identification of Clinical Candidate 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for ...Title: Discovery of a Novel Class of Phosphodiesterase 10A Inhibitors and Identification of Clinical Candidate 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the Treatment of Schizophrenia
Authors: Verhoest, P.R. / Chapin, D.S. / Corman, M. / Fonseca, K. / Harms, J.F. / Hou, X. / Marr, E.S. / Menniti, F.S. / Nelson, F. / O'Connor, R. / Pandit, J. / Proulx-Lafrance, C. / Schmidt, A.W. / ...Authors: Verhoest, P.R. / Chapin, D.S. / Corman, M. / Fonseca, K. / Harms, J.F. / Hou, X. / Marr, E.S. / Menniti, F.S. / Nelson, F. / O'Connor, R. / Pandit, J. / Proulx-Lafrance, C. / Schmidt, A.W. / Schmidt, C.J. / Suiciak, J.A. / Liras, S.
History
DepositionJun 8, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 4, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / 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_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.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_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_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_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,3266
Polymers43,6661
Non-polymers6605
Water3,783210
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)120.917, 120.917, 83.946
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number146
Space group name H-MH3

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Components

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Protein , 1 types, 1 molecules A

#1: Protein cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A


Mass: 43665.988 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Pde10a / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf21
References: UniProt: Q9QYJ6, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase

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Non-polymers , 5 types, 215 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-PF8 / 2-{[4-(4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy]methyl}quinoline


Mass: 378.426 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H18N4O
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 210 / 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: 2.7 Å3/Da / Density % sol: 54.52 %

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Data collection

Diffraction
IDMean temperature (K)Crystal-ID
11001
21
Diffraction source
SourceTypeIDWavelength (Å)
ROTATING ANODERigaku FRE11.54
2
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.7→38.96 Å / Num. obs: 48897 / % possible obs: 97.1 % / Redundancy: 5.05 % / Rmerge(I) obs: 0.075 / Χ2: 0.96 / Scaling rejects: 1865
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2% possible all
1.7-1.762.480.3013.1961038770.9177.1
1.76-1.833.230.3113.51535447600.8994.1
1.83-1.9150.3124.32504450071.0399.9
1.91-2.025.440.27352757650641.06100
2.02-2.145.480.1936.52746349991.02100
2.14-2.315.560.1388.92808850360.99100
2.31-2.545.610.10311.82847750510.94100
2.54-2.915.650.07615.72863750300.92100
2.91-3.665.660.05421.92896050400.92100
3.66-38.965.660.04129.32935650330.9100

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Processing

Software
NameVersionClassificationNB
d*TREK8.0SSIdata scaling
REFMACrefinement
PDB_EXTRACT3.005data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2O8H

2o8h


Resolution: 1.7→38.96 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.939 / WRfactor Rfree: 0.247 / WRfactor Rwork: 0.233 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.82 / SU B: 2.197 / SU ML: 0.072 / SU R Cruickshank DPI: 0.115 / SU Rfree: 0.108 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.1 / ESU R Free: 0.097 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.224 3772 7.7 %RANDOM
Rwork0.2 ---
obs0.201 48892 97.09 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 48.98 Å2 / Biso mean: 20.41 Å2 / Biso min: 11.49 Å2
Baniso -1Baniso -2Baniso -3
1--0.41 Å2-0.2 Å20 Å2
2---0.41 Å20 Å2
3---0.61 Å2
Refinement stepCycle: LAST / Resolution: 1.7→38.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2488 0 41 210 2739
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222591
X-RAY DIFFRACTIONr_angle_refined_deg1.1791.9643511
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.7675306
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.98923.71124
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.02615450
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.091517
X-RAY DIFFRACTIONr_chiral_restr0.0770.2377
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021968
X-RAY DIFFRACTIONr_nbd_refined0.1990.21327
X-RAY DIFFRACTIONr_nbtor_refined0.2970.21789
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1090.2179
X-RAY DIFFRACTIONr_metal_ion_refined0.0340.21
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1860.245
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1730.219
X-RAY DIFFRACTIONr_mcbond_it0.6781.51594
X-RAY DIFFRACTIONr_mcangle_it1.03822479
X-RAY DIFFRACTIONr_scbond_it1.70331170
X-RAY DIFFRACTIONr_scangle_it2.644.51032
LS refinement shellResolution: 1.7→1.744 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.372 207 -
Rwork0.335 2583 -
all-2790 -
obs--74.64 %

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