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- PDB-5c2e: PDE10 complexed with6-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]... -

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Basic information

Entry
Database: PDB / ID: 5c2e
TitlePDE10 complexed with6-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]-5-methyl-2-[2-(2-pyridyl)ethoxy]pyrimidin-4-amine
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Keywordshydrolase/hydrolase inhibitor / Phosphodiesterase / inhibitor / complex / hydrolase-hydrolase inhibitor complex
Function / homology
Function and homology information


3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cAMP catabolic process / regulation of cAMP/PKA signal transduction / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / cGMP binding ...3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cAMP catabolic process / regulation of cAMP/PKA signal transduction / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / : / cAMP binding / G alpha (s) signalling events / glutamatergic 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 / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / GAF-like domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-4PX / Chem-4Y1 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.1 Å
AuthorsYan, Y.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis.
Authors: Shipe, W.D. / Sharik, S.S. / Barrow, J.C. / McGaughey, G.B. / Theberge, C.R. / Uslaner, J.M. / Yan, Y. / Renger, J.J. / Smith, S.M. / Coleman, P.J. / Cox, C.D.
History
DepositionJun 15, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 2, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 27, 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 / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / pdbx_struct_oper_list / struct_conn
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _pdbx_struct_oper_list.symmetry_operation / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _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_asym_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
Revision 1.2Mar 13, 2024Group: Source and taxonomy / Category: entity_src_gen

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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)83,9118
Polymers82,9912
Non-polymers9206
Water2,108117
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,9364
Polymers41,4961
Non-polymers4403
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)41,9754
Polymers41,4961
Non-polymers4803
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.500, 81.350, 158.400
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 41495.504 Da / Num. of mol.: 2 / Fragment: catalytic domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Production host: Escherichia coli (E. coli)
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase

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Non-polymers , 5 types, 123 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
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-4PX / 3-(1-hydroxy-2-methylpropan-2-yl)-5-phenyl-3,5-dihydro-1H-imidazo[4,5-c][1,8]naphthyridine-2,4-dione


Mass: 350.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H18N4O3
#5: Chemical ChemComp-4Y1 / 6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[2-(pyridin-2-yl)ethoxy]pyrimidin-4-amine


Mass: 389.902 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20ClN5OS
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 117 / 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: 1.88 Å3/Da / Density % sol: 34.42 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 100mM HEPES pH 7.0, 20% PEG3350, 200mM MgCl2, and 10mM 2-Mercaptoethanol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 8, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 38492 / % possible obs: 97.9 % / Redundancy: 4.6 % / Biso Wilson estimate: 37.03 Å2 / Rmerge(I) obs: 0.076 / Χ2: 1.105 / Net I/av σ(I): 17.496 / Net I/σ(I): 12.4 / Num. measured all: 176601
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.1-2.184.80.46738280.97699.8
2.18-2.264.70.38838461.19199.6
2.26-2.374.70.32938551.19799.4
2.37-2.494.70.23538571.06199.4
2.49-2.654.60.17338691.24499.2
2.65-2.854.50.13538661.14499.4
2.85-3.144.50.09538801.12198.7
3.14-3.594.30.06538850.95598.6
3.59-4.524.20.05238171.01695.8
4.52-504.80.04437891.12490.2

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Processing

Software
NameVersionClassification
BUSTER-TNTrefinement
SCALEPACKdata scaling
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2OUN

2oun


Resolution: 2.1→40.96 Å / Cor.coef. Fo:Fc: 0.8794 / Cor.coef. Fo:Fc free: 0.8589 / SU R Cruickshank DPI: 0.296 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.297 / SU Rfree Blow DPI: 0.219 / SU Rfree Cruickshank DPI: 0.22
RfactorNum. reflection% reflectionSelection details
Rfree0.2801 1934 5.04 %RANDOM
Rwork0.2489 ---
obs0.2505 38368 97.1 %-
Displacement parametersBiso max: 121.32 Å2 / Biso mean: 49.28 Å2 / Biso min: 22.22 Å2
Baniso -1Baniso -2Baniso -3
1--25.1549 Å20 Å20 Å2
2--16.2175 Å20 Å2
3---8.9374 Å2
Refine analyzeLuzzati coordinate error obs: 0.406 Å
Refinement stepCycle: final / Resolution: 2.1→40.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5215 0 56 117 5388
Biso mean--43.95 39.69 -
Num. residues----646
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1871SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes128HARMONIC8
X-RAY DIFFRACTIONt_gen_planes788HARMONIC8
X-RAY DIFFRACTIONt_it5402HARMONIC20
X-RAY DIFFRACTIONt_nbd3SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion696SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact6482SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5402HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg7323HARMONIC20.98
X-RAY DIFFRACTIONt_omega_torsion1.47
X-RAY DIFFRACTIONt_other_torsion18.14
LS refinement shellResolution: 2.09→2.15 Å / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.3108 143 5.27 %
Rwork0.2849 2572 -
all0.2862 2715 -
obs--97.1 %

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