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- PDB-4ddl: PDE10a Crystal Structure Complexed with Novel Inhibitor -

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Basic information

Entry
Database: PDB / ID: 4ddl
TitlePDE10a Crystal Structure Complexed with Novel Inhibitor
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHydrolase/Hydrolase Inhibitor / Phosphodiesterase 10a / Hydrolase / 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 / 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-0JQ / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.07 Å
AuthorsChmait, S. / Jordan, S. / Zhang, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Discovery of potent, selective, and metabolically stable 4-(pyridin-3-yl)cinnolines as novel phosphodiesterase 10A (PDE10A) inhibitors.
Authors: Hu, E. / Kunz, R.K. / Rumfelt, S. / Chen, N. / Burli, R. / Li, C. / Andrews, K.L. / Zhang, J. / Chmait, S. / Kogan, J. / Lindstrom, M. / Hitchcock, S.A. / Treanor, J.
History
DepositionJan 18, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 21, 2012Provider: repository / Type: Initial release

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Structure visualization

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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)80,32723
Polymers77,7792
Non-polymers2,54821
Water5,693316
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)120,34633
Polymers116,6693
Non-polymers3,67730
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 area4610 Å2
ΔGint-262 kcal/mol
Surface area41300 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)120,63436
Polymers116,6693
Non-polymers3,96633
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555-z,-x,y1
crystal symmetry operation10_555-y,z,-x1
Buried area4580 Å2
ΔGint-264 kcal/mol
Surface area39110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)252.964, 252.964, 252.964
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number196
Space group name H-MF23
Components on special symmetry positions
IDModelComponents
11A-1189-

HOH

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Components

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


Mass: 38889.586 Da / Num. of mol.: 2 / Fragment: human PDE10a, residues 442-779
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.: 4 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-0JQ / 2-{1-[5-(6,7-dimethoxycinnolin-4-yl)-3-methylpyridin-2-yl]piperidin-4-yl}propan-2-ol


Mass: 422.520 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H30N4O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 316 / 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: 4.34 Å3/Da / Density % sol: 71.63 %
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, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jan 7, 2012 / Details: Osmics VariMax HR
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.06→30 Å / Num. all: 81673 / Num. obs: 80952 / % possible obs: 99.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0

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Processing

Software
NameVersionClassification
StructureStudiodata collection
REFMAC5.6.0117refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.07→30 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.949 / SU B: 4.511 / SU ML: 0.066 / Cross valid method: THROUGHOUT / ESU R: 0.124 / ESU R Free: 0.11
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.1954 4110 5 %RANDOM
Rwork0.18568 ---
all0.18619 77380 --
obs0.18619 77380 99.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 30.711 Å2
Refinement stepCycle: LAST / Resolution: 2.07→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5081 0 141 316 5538
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.025337
X-RAY DIFFRACTIONr_angle_refined_deg1.3141.9767245
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.35624
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.53224.049247
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.12615924
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.0641528
X-RAY DIFFRACTIONr_chiral_restr0.1340.2794
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0213972
LS refinement shellResolution: 2.066→2.12 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.196 293 -
Rwork0.182 5500 -
obs--98.84 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.97480.11640.02840.62080.1210.46720.0063-0.0081-0.0720.0548-0.01690.00380.0181-0.01820.01060.0346-0.00970.00910.0130.01520.03923.31490.49229.86
20.81040.21020.11681.0240.04870.431-0.00660.0691-0.0405-0.02830.0143-0.0464-0.00850.0101-0.00770.025-0.01750.01540.0510.01020.0282-27.16958.59930.242
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A442 - 759
2X-RAY DIFFRACTION1A1001 - 1009
3X-RAY DIFFRACTION2B452 - 759
4X-RAY DIFFRACTION2B801 - 810

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