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- PDB-3lxg: Crystal structure of rat phosphodiesterase 10A in complex with li... -

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Basic information

Entry
Database: PDB / ID: 3lxg
TitleCrystal structure of rat phosphodiesterase 10A in complex with ligand WEB-3
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE / PHOSPHODIESTERASE 10A / CATALYTIC DOMAIN / Allosteric enzyme / cAMP / cAMP-binding / cGMP / cGMP-binding / Metal-binding / Nucleotide-binding
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-Z73 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLPREP / Resolution: 2.3 Å
AuthorsMosbacher, T. / Jestel, A. / Steinbacher, S.
CitationJournal: J.Med.Chem. / Year: 2010
Title: Discovery of imidazo[1,5-a]pyrido[3,2-e]pyrazines as a new class of phosphodiesterase 10A inhibitiors.
Authors: Hofgen, N. / Stange, H. / Schindler, R. / Lankau, H.J. / Grunwald, C. / Langen, B. / Egerland, U. / Tremmel, P. / Pangalos, M.N. / Marquis, K.L. / Hage, T. / Harrison, B.L. / Malamas, M.S. / ...Authors: Hofgen, N. / Stange, H. / Schindler, R. / Lankau, H.J. / Grunwald, C. / Langen, B. / Egerland, U. / Tremmel, P. / Pangalos, M.N. / Marquis, K.L. / Hage, T. / Harrison, B.L. / Malamas, M.S. / Brandon, N.J. / Kronbach, T.
History
DepositionFeb 25, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 19, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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_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.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_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

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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)36,0334
Polymers35,6731
Non-polymers3603
Water2,126118
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules

A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules

A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,09912
Polymers107,0193
Non-polymers1,0809
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-y,x-y,z1
crystal symmetry operation3_555-x+y,-x,z1
Buried area4050 Å2
ΔGint-22 kcal/mol
Surface area39080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.149, 120.149, 83.119
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

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


Mass: 35673.043 Da / Num. of mol.: 1 / Fragment: residues 463-770
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Pde10a / Cell (production host): Sf9 insect cells / Production host: baculovirus
References: UniProt: Q9QYJ6, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-Z73 / 2-methoxy-6,7-dimethyl-9-propylimidazo[1,5-a]pyrido[3,2-e]pyrazine


Mass: 270.330 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H18N4O
#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: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 118 / 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: 3.33 Å3/Da / Density % sol: 63.11 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: PEG, pH 6.5, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.947 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Oct 20, 2006 / Details: LN2 COOLED FIXED-EXIT
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.947 Å / Relative weight: 1
ReflectionResolution: 2.3→64.96 Å / Num. all: 18763 / Num. obs: 19899 / % possible obs: 94.3 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Rmerge(I) obs: 0.068 / Net I/σ(I): 9
Reflection shellResolution: 2.3→2.42 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.523 / Mean I/σ(I) obs: 1.4 / % possible all: 71.5

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLPREP / Resolution: 2.3→64.96 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.934 / SU B: 6.927 / SU ML: 0.16 / Cross valid method: THROUGHOUT / ESU R: 0.256 / ESU R Free: 0.211 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22851 969 5.2 %RANDOM
Rwork0.1759 ---
all0.1775 18762 --
obs0.17851 17793 94.29 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 39.704 Å2
Baniso -1Baniso -2Baniso -3
1--1.87 Å2-0.93 Å20 Å2
2---1.87 Å20 Å2
3---2.8 Å2
Refinement stepCycle: LAST / Resolution: 2.3→64.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2499 0 22 118 2639
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222603
X-RAY DIFFRACTIONr_bond_other_d0.0020.021754
X-RAY DIFFRACTIONr_angle_refined_deg1.0561.9653532
X-RAY DIFFRACTIONr_angle_other_deg0.85334261
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0175309
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.04223.871124
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.64515446
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4881516
X-RAY DIFFRACTIONr_chiral_restr0.0570.2379
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022868
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02533
X-RAY DIFFRACTIONr_nbd_refined0.2030.2649
X-RAY DIFFRACTIONr_nbd_other0.1740.21847
X-RAY DIFFRACTIONr_nbtor_refined0.1790.21307
X-RAY DIFFRACTIONr_nbtor_other0.0850.21259
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1260.2123
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined0.0930.22
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1960.211
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1830.236
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1130.26
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.98222035
X-RAY DIFFRACTIONr_mcbond_other0.3572619
X-RAY DIFFRACTIONr_mcangle_it2.44832500
X-RAY DIFFRACTIONr_scbond_it3.60541349
X-RAY DIFFRACTIONr_scangle_it5.0861032
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.366 47 -
Rwork0.283 964 -
obs--67.76 %

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