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- PDB-4ael: PDE10A in complex with the inhibitor AZ5 -

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Basic information

Entry
Database: PDB / ID: 4ael
TitlePDE10A in complex with the inhibitor AZ5
ComponentsCAMP AND CAMP-INHIBITED CGMP 3', 5'-CYCLIC PHOSPHODIESTERASE 10A
KeywordsHYDROLASE / HIT-TO-LEAD / ENZYME INHIBITOR / NAPHTYRIDINE
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-4HN / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsBauer, U. / Giordanetto, F. / Bauer, M. / OMahony, G. / Johansson, K.E. / Knecht, W. / Hartleib-Geschwindner, J. / Toppner Carlsson, E. / Enroth, C. / Sjogren, T.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Discovery of 4-Hydroxy-1,6-Naphthyridine-3-Carbonitrile Derivatives as Novel Pde10A Inhibitors.
Authors: Bauer, U. / Giordanetto, F. / Bauer, M. / O'Mahony, G. / Johansson, K.E. / Knecht, W. / Hartleib-Geschwindner, J. / Carlsson, E.T. / Enroth, C.
History
DepositionJan 11, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 25, 2012Provider: repository / Type: Initial release
Revision 1.1Aug 15, 2012Group: Database references
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.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)79,8458
Polymers78,9302
Non-polymers9146
Water5,639313
1
A: CAMP AND CAMP-INHIBITED CGMP 3', 5'-CYCLIC PHOSPHODIESTERASE 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9224
Polymers39,4651
Non-polymers4573
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)39,9224
Polymers39,4651
Non-polymers4573
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.966, 81.688, 160.469
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


Mass: 39465.215 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN, RESIDUES 438-779
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli)
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-4HN / 2-(2'-ETHOXYBIPHENYL-4-YL)-4-HYDROXY-1,6-NAPHTHYRIDINE-3-CARBONITRILE


Mass: 367.400 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H17N3O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 313 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer details2-(2'-ETHOXYBIPHENYL-4-YL)-4-HYDROXY-1, 6-NAPHTHYRIDINE-3-CARBONITRILE (4HN): HET COMPOUND ALIAS IN ...2-(2'-ETHOXYBIPHENYL-4-YL)-4-HYDROXY-1, 6-NAPHTHYRIDINE-3-CARBONITRILE (4HN): HET COMPOUND ALIAS IN MAIN REF IS AZ5
Sequence detailsTHE FIRST THREE RESIDUES ORIGINATES FROM VECTOR

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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: 2.14 Å3/Da / Density % sol: 42.4 % / Description: NONE
Crystal growpH: 7.5
Details: 20 MM TRIS PH 7.5, 100 MM NACL AND 10 MM BETA MERCAPTOETHANOL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.98
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 26, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.2→40 Å / Num. obs: 30061 / % possible obs: 88.4 % / Observed criterion σ(I): 2 / Redundancy: 4.5 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 13.4
Reflection shellResolution: 2.2→2.26 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.36 / Mean I/σ(I) obs: 4.1 / % possible all: 83

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2OUP

2oup


Resolution: 2.2→50 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.935 / Cross valid method: THROUGHOUT / ESU R: 0.461 / ESU R Free: 0.258 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.24169 1454 5 %RANDOM
Rwork0.18683 ---
obs0.18955 27452 84.46 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 43.49 Å2
Baniso -1Baniso -2Baniso -3
1-3.61 Å20 Å20 Å2
2---2.55 Å20 Å2
3----1.06 Å2
Refinement stepCycle: LAST / Resolution: 2.2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5206 0 60 313 5579
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.025396
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6711.967310
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8015641
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.86224.104251
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.66215946
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.521528
X-RAY DIFFRACTIONr_chiral_restr0.1240.2796
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0214166
X-RAY DIFFRACTIONr_gen_planes_other
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
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: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.323 91 -
Rwork0.248 1760 -
obs--74.73 %

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