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- PDB-3hr1: Discovery of novel inhibitors of PDE10A -

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Basic information

Entry
Database: PDB / ID: 3hr1
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


cyclic-nucleotide phosphodiesterase activity / cGMP effects / G alpha (s) signalling events / extrinsic component of postsynaptic density membrane / regulation of protein kinase A signaling / negative regulation of cAMP-mediated signaling / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling ...cyclic-nucleotide phosphodiesterase activity / cGMP effects / G alpha (s) signalling events / extrinsic component of postsynaptic density membrane / regulation of protein kinase A signaling / negative regulation of cAMP-mediated signaling / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 3',5'-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-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / cAMP-mediated signaling / perikaryon / neuronal cell body / glutamatergic synapse / synapse / 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-PF9 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.53 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

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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)44,3406
Polymers43,6661
Non-polymers6745
Water8,215456
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)120.660, 120.660, 83.210
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, 461 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-PF9 / 2-{[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy]methyl}quinoline


Mass: 392.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H20N4O / Comment: inhibitor*YM
#4: Chemical ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 456 / 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: 2.67 Å3/Da / Density % sol: 53.93 %

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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: 1.53→44.25 Å / Num. all: 67918 / Num. obs: 57998 / % possible obs: 85.4 % / Observed criterion σ(I): 3
Reflection shellResolution: 1.53→1.59 Å / % possible all: 17.5

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Processing

Software
NameVersionClassificationNB
d*TREKdata scaling
REFMACrefinement
PDB_EXTRACT3.005data extraction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2O8H

2o8h


Resolution: 1.53→44.25 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.955 / WRfactor Rfree: 0.2 / WRfactor Rwork: 0.175 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.858 / SU B: 1.627 / SU ML: 0.058 / SU R Cruickshank DPI: 0.082 / SU Rfree: 0.083 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.082 / ESU R Free: 0.083 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.211 4479 7.7 %RANDOM
Rwork0.184 ---
obs0.186 57989 85.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 98.66 Å2 / Biso mean: 23.128 Å2 / Biso min: 12.05 Å2
Baniso -1Baniso -2Baniso -3
1--0.64 Å2-0.32 Å20 Å2
2---0.64 Å20 Å2
3---0.96 Å2
Refinement stepCycle: LAST / Resolution: 1.53→44.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2488 0 42 456 2986
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222592
X-RAY DIFFRACTIONr_angle_refined_deg1.1791.9643513
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.675306
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.88423.71124
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.19115450
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.3181517
X-RAY DIFFRACTIONr_chiral_restr0.0780.2377
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021969
X-RAY DIFFRACTIONr_nbd_refined0.2050.21407
X-RAY DIFFRACTIONr_nbtor_refined0.3020.21806
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1430.2336
X-RAY DIFFRACTIONr_metal_ion_refined0.0440.21
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2030.257
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1850.234
X-RAY DIFFRACTIONr_mcbond_it0.7361.51586
X-RAY DIFFRACTIONr_mcangle_it1.10422479
X-RAY DIFFRACTIONr_scbond_it1.86231178
X-RAY DIFFRACTIONr_scangle_it2.94.51034
LS refinement shellResolution: 1.532→1.572 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.429 65 -
Rwork0.357 586 -
all-651 -
obs--12.98 %

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