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- PDB-4tpp: 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors -

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Basic information

Entry
Database: PDB / ID: 4tpp
Title2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHydrolase/Hydrolase Inhibitor / Phosphodiesterase 10A / Quinolines / Hydrolase-Hydrolase Inhibitor complex
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 / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 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 / 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 / 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-35D / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.65 Å
AuthorsChmait, S.
CitationJournal: Bioorg.Med.Chem. / Year: 2014
Title: Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility.
Authors: Rzasa, R.M. / Frohn, M.J. / Andrews, K.L. / Chmait, S. / Chen, N. / Clarine, J.G. / Davis, C. / Eastwood, H.A. / Horne, D.B. / Hu, E. / Jones, A.D. / Kaller, M.R. / Kunz, R.K. / Miller, S. / ...Authors: Rzasa, R.M. / Frohn, M.J. / Andrews, K.L. / Chmait, S. / Chen, N. / Clarine, J.G. / Davis, C. / Eastwood, H.A. / Horne, D.B. / Hu, E. / Jones, A.D. / Kaller, M.R. / Kunz, R.K. / Miller, S. / Monenschein, H. / Nguyen, T. / Pickrell, A.J. / Porter, A. / Reichelt, A. / Zhao, X. / Treanor, J.J. / Allen, J.R.
History
DepositionJun 9, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 17, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2015Group: Data collection
Revision 1.2Nov 22, 2017Group: Derived calculations / Refinement description / Category: pdbx_struct_oper_list / software / Item: _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 27, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)83,46820
Polymers81,1512
Non-polymers2,31718
Water1,838102
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)125,77336
Polymers121,7263
Non-polymers4,04733
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation18_555z,-x+1/2,-y+1/21
crystal symmetry operation48_555-y+1/2,-z+1/2,x1
Buried area5210 Å2
ΔGint-263 kcal/mol
Surface area38570 Å2
MethodPISA
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules

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

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


Theoretical massNumber of molelcules
Total (without water)124,63224
Polymers121,7263
Non-polymers2,90621
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555-z,-x,y1
crystal symmetry operation10_555-y,z,-x1
Buried area4610 Å2
ΔGint-264 kcal/mol
Surface area39070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)253.216, 253.216, 253.216
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number196
Space group name H-MF23
Components on special symmetry positions
IDModelComponents
11B-803-

SO4

21A-1107-

HOH

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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: 40575.398 Da / Num. of mol.: 2 / Fragment: UNP residues 452-789
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, 120 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-35D / 1-[4-(3-{[1-(quinolin-2-yl)azetidin-3-yl]oxy}quinoxalin-2-yl)piperidin-1-yl]ethanone


Mass: 453.536 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H27N5O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 102 / 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: 4.17 Å3/Da / Density % sol: 74.17 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 1.6M Ammonium Sulfate, 0.1M MES monohydrate, 10% v/v 1,4-Dioxane, pH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 26, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
Reflection twinOperator: k,h,-l / Fraction: 0.44
ReflectionResolution: 2.65→48.731 Å / Num. obs: 38939 / % possible obs: 99.9 % / Redundancy: 13.2 % / Χ2: 1.006 / Net I/σ(I): 3.3 / Num. measured all: 511963
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.65-2.7413.10.96338900.996100
2.74-2.8513.10.75238611.003100
2.85-2.9813.20.50638761100
2.98-3.1413.30.36138471.013100
3.14-3.3413.30.2438661.003100
3.34-3.613.30.14438840.985100
3.6-3.9613.30.11138960.993100
3.96-4.53130.10138781.067100
4.53-5.7112.90.08339201.038100
5.71-5012.90.04540060.96399.9

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.14data extraction
PHENIX(phenix.refine: 1.9_1692)refinement
RefinementResolution: 2.65→48.731 Å / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.06 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflection
Rfree0.1977 1869 4.8 %
Rwork0.1671 --
obs0.1697 38924 99.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 138.28 Å2 / Biso mean: 54.7512 Å2 / Biso min: 26.16 Å2
Refinement stepCycle: final / Resolution: 2.65→48.731 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4963 0 133 102 5198
Biso mean--72.73 52.14 -
Num. residues----612

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