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- PDB-2y0j: Triazoloquinazolines as a novel class of phosphodiesterase 10A (P... -

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Basic information

Entry
Database: PDB / ID: 2y0j
TitleTriazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors, part 2, Lead-optimisation.
ComponentsCAMP AND CAMP-INHIBITED CGMP 3', 5'-CYCLIC PHOSPHODIESTERASE 10A
KeywordsHYDROLASE
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 / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / 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 / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / 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-AXC / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.43 Å
AuthorsKehler, J. / Ritzen, A. / Langgard, M. / Petersen, S.L. / Christoffersen, C.T. / Nielsen, J. / Kilburn, J.P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Triazoloquinazolines as a Novel Class of Phosphodiesterase 10A (Pde10A) Inhibitors.
Authors: Kehler, J. / Ritzen, A. / Langgard, M. / Petersen, S.L. / Farah, M.M. / Bundgaard, C. / Christoffersen, C.T. / Nielsen, J. / Kilburn, J.P.
History
DepositionDec 3, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 15, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / 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_database_status.status_code_sf / _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_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)80,1258
Polymers79,2532
Non-polymers8726
Water3,963220
1
A: CAMP AND CAMP-INHIBITED CGMP 3', 5'-CYCLIC PHOSPHODIESTERASE 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0634
Polymers39,6271
Non-polymers4363
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)40,0634
Polymers39,6271
Non-polymers4363
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.380, 81.690, 160.620
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: 39626.531 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN, RESIDUES 432-764
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase
#2: Chemical ChemComp-AXC / 5-(1H-BENZIMIDAZOL-2-YLMETHYLSULFANYL)-2-METHYL-[1,2,4]TRIAZOLO[1,5-C]QUINAZOLINE


Mass: 346.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H14N6S
#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.: 220 / 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: 2.25 Å3/Da / Density % sol: 45.36 % / Description: NONE
Crystal growpH: 8.9 / Details: 100 MM TRIS-HCL PH8.9, 5 MM CACL2, 11-12% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418
DetectorType: RIGAKU IMAGE PLATE / Detector: IMAGE PLATE / Date: Sep 13, 2007 / Details: MIRRORS
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.43→57.27 Å / Num. obs: 25010 / % possible obs: 99.1 % / Observed criterion σ(I): 2 / Redundancy: 3.1 % / Biso Wilson estimate: 37.5 Å2 / Rmerge(I) obs: 0.14 / Net I/σ(I): 5.6
Reflection shellResolution: 2.43→2.56 Å / Redundancy: 3 % / Rmerge(I) obs: 0.46 / Mean I/σ(I) obs: 2 / % possible all: 94.1

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Processing

Software
NameVersionClassification
REFMAC5.5.0110refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2O8H

2o8h


Resolution: 2.43→47.2 Å / Cor.coef. Fo:Fc: 0.918 / Cor.coef. Fo:Fc free: 0.866 / SU B: 10.596 / SU ML: 0.246 / Cross valid method: THROUGHOUT / ESU R: 0.835 / ESU R Free: 0.336 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY.
RfactorNum. reflection% reflectionSelection details
Rfree0.28445 1287 5.2 %RANDOM
Rwork0.2209 ---
obs0.22412 23564 98.41 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.825 Å2
Baniso -1Baniso -2Baniso -3
1-0.79 Å20 Å20 Å2
2---2.09 Å20 Å2
3---1.3 Å2
Refinement stepCycle: LAST / Resolution: 2.43→47.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5016 0 54 220 5290
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0225228
X-RAY DIFFRACTIONr_bond_other_d0.0010.023458
X-RAY DIFFRACTIONr_angle_refined_deg1.0091.9667103
X-RAY DIFFRACTIONr_angle_other_deg0.8333.0018393
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0985626
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.4724.093237
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.8815875
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.3581525
X-RAY DIFFRACTIONr_chiral_restr0.0570.2776
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0215758
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021054
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.3921.53134
X-RAY DIFFRACTIONr_mcbond_other0.0531.51258
X-RAY DIFFRACTIONr_mcangle_it0.73125063
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.87732094
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it1.4684.52040
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: 2.431→2.494 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.366 104 -
Rwork0.286 1671 -
obs--96.94 %

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