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- PDB-4hf4: Crystal Structure of PDE10A with a biaryl ether inhibitor (1-(1-(... -

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Basic information

Entry
Database: PDB / ID: 4hf4
TitleCrystal Structure of PDE10A with a biaryl ether inhibitor (1-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-4-yl)ethanol)
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PDE10A / phosphodiesterase 10A / biaryl ethers / 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-15H / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsChmait, S. / Jordan, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Discovery of selective biaryl ethers as PDE10A inhibitors: Improvement in potency and mitigation of Pgp-mediated efflux.
Authors: Rzasa, R.M. / Hu, E. / Rumfelt, S. / Chen, N. / Andrews, K.L. / Chmait, S. / Falsey, J.R. / Zhong, W. / Jones, A.D. / Porter, A. / Louie, S.W. / Zhao, X. / Treanor, J.J. / Allen, J.R.
History
DepositionOct 4, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 12, 2012Provider: repository / Type: Initial release

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


Theoretical massNumber of molelcules
Total (without water)76,40524
Polymers73,7152
Non-polymers2,69022
Water9,278515
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)114,88939
Polymers110,5723
Non-polymers4,31736
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-261 kcal/mol
Surface area41020 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)114,32533
Polymers110,5723
Non-polymers3,75230
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555-z,-x,y1
crystal symmetry operation10_555-y,z,-x1
Buried area4600 Å2
ΔGint-264 kcal/mol
Surface area39100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)252.879, 252.879, 252.879
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-1183-

HOH

21A-1308-

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: 36857.441 Da / Num. of mol.: 2
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, 537 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 / Sulfate


Mass: 96.063 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-15H / (1S)-1-(1-{3-[4-(1,3-benzothiazol-2-ylamino)phenoxy]pyrazin-2-yl}piperidin-4-yl)ethanol


Mass: 447.553 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H25N5O2S
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 515 / 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: 4.57 Å3/Da / Density % sol: 73.09 %
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: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1.0001 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 2, 2012
RadiationMonochromator: Double-crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0001 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. all: 89616 / Num. obs: 89599 / % possible obs: 99.98 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 2→2.07 Å / % possible all: 100

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
MOLREP9.2.10phasing
REFMAC5.6.0117refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→30 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.957 / SU B: 4.001 / SU ML: 0.061 / Cross valid method: THROUGHOUT / ESU R: 0.109 / ESU R Free: 0.104
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.19692 4482 5 %RANDOM
Rwork0.17586 ---
all0.17691 85151 --
obs0.17691 85049 99.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 37.435 Å2
Refinement stepCycle: LAST / Resolution: 2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5081 0 149 515 5745
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.025346
X-RAY DIFFRACTIONr_angle_refined_deg1.0661.9767250
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.0745624
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.19124.049247
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.15915924
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.0151528
X-RAY DIFFRACTIONr_chiral_restr0.090.2795
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0213980
LS refinement shellResolution: 2.002→2.054 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.153 299 -
Rwork0.146 6092 -
obs--99.21 %
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)
10.97280.11060.04230.49650.09030.40460.0041-0.0081-0.06260.0463-0.01670.00980.0186-0.01650.01260.0425-0.01520.01820.01620.01250.04563.292790.50829.9806
20.70990.16610.08350.98180.04490.3376-0.00010.0563-0.0341-0.05380.008-0.0325-0.01160.011-0.00790.0288-0.02130.01690.06210.01220.0312-27.103658.611330.0842
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 DIFFRACTION2A1010
5X-RAY DIFFRACTION2B801 - 809

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