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- PDB-5c28: PDE10 complexed with 6-chloro-2-cyclopropyl-5-methyl-pyrimidin-4-amine -

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Basic information

Entry
Database: PDB / ID: 5c28
TitlePDE10 complexed with 6-chloro-2-cyclopropyl-5-methyl-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 cGMP-mediated signaling / cGMP catabolic process / cGMP effects / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity ...3',5'-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 / 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 / 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 / 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
6-chloro-2-cyclopropyl-5-methylpyrimidin-4-amine / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.56 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 1.0Sep 30, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 21, 2015Group: Database references
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / 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_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

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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)83,3547
Polymers82,9912
Non-polymers3635
Water10,359575
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,7694
Polymers41,4961
Non-polymers2733
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)41,5853
Polymers41,4961
Non-polymers902
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.650, 82.040, 152.860
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 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
#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-4XV / 6-chloro-2-cyclopropyl-5-methylpyrimidin-4-amine


Mass: 183.638 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H10ClN3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 575 / 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, 20% PEG3350, 200mM MgCl2, and 10mM 2-Mercaptoethanol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / 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: 1.56→50 Å / Num. obs: 88979 / % possible obs: 98.7 % / Redundancy: 6.2 % / Biso Wilson estimate: 19.47 Å2 / Rmerge(I) obs: 0.051 / Χ2: 0.968 / Net I/av σ(I): 28.013 / Net I/σ(I): 15.2 / Num. measured all: 548846
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.56-1.625.40.32783400.88893.9
1.62-1.6860.26887580.95798.6
1.68-1.7660.20987761.03698.5
1.76-1.8560.15887871.198.1
1.85-1.975.90.1288381.09598.9
1.97-2.125.90.09388921.10299.2
2.12-2.336.10.07289641.07299.8
2.33-2.676.50.05790650.9299.9
2.67-3.366.90.04791060.841100
3.36-506.90.03194530.74999.6

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
BUSTER-TNTrefinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
REFMACphasing
RefinementResolution: 1.56→22.84 Å / Cor.coef. Fo:Fc: 0.9558 / Cor.coef. Fo:Fc free: 0.9441 / SU R Cruickshank DPI: 0.079 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.083 / SU Rfree Blow DPI: 0.08 / SU Rfree Cruickshank DPI: 0.078
RfactorNum. reflection% reflectionSelection details
Rfree0.1956 4453 5.01 %RANDOM
Rwork0.1704 ---
obs0.1717 88802 99.01 %-
Displacement parametersBiso max: 117.23 Å2 / Biso mean: 22.35 Å2 / Biso min: 9.1 Å2
Baniso -1Baniso -2Baniso -3
1--4.7473 Å20 Å20 Å2
2--2.3832 Å20 Å2
3---2.3641 Å2
Refine analyzeLuzzati coordinate error obs: 0.155 Å
Refinement stepCycle: final / Resolution: 1.56→22.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5165 0 16 575 5756
Biso mean--21.27 31.3 -
Num. residues----642
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1861SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes129HARMONIC8
X-RAY DIFFRACTIONt_gen_planes769HARMONIC8
X-RAY DIFFRACTIONt_it5327HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion699SEMIHARMONIC5
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_contact6844SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5327HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg7224HARMONIC20.98
X-RAY DIFFRACTIONt_omega_torsion2.61
X-RAY DIFFRACTIONt_other_torsion15.42
LS refinement shellResolution: 1.56→1.6 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2278 306 4.84 %
Rwork0.1868 6010 -
all0.1887 6316 -
obs--99.01 %

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