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- PDB-4ajg: Identification and structural characterization of PDE10 fragment ... -

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Basic information

Entry
Database: PDB / ID: 4ajg
TitleIdentification and structural characterization of PDE10 fragment inhibitors
ComponentsCAMP AND CAMP-INHIBITED CGMP 3', 5'-CYCLIC PHOSPHODIESTERASE 10A
KeywordsHYDROLASE
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-GMP phosphodiesterase activity / cGMP binding / 3',5'-cyclic-nucleotide 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-GMP phosphodiesterase activity / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / G alpha (s) signalling events / signal transduction / metal ion binding / cytosol
Similarity search - Function
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / GAF domain / 3'5'-cyclic nucleotide phosphodiesterase / Domain present in phytochromes and cGMP-specific phosphodiesterases. / 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. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / GAF domain / 3'5'-cyclic nucleotide phosphodiesterase / Domain present in phytochromes and cGMP-specific phosphodiesterases. / 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 / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
THIENO[3,2-C][1,6]NAPHTHYRIDINE / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsJohansson, P. / Albert, J.S. / Spadola, L. / Akerud, T. / Back, E. / Hillertz, P. / Horsefeld, R. / Scott, C. / Spear, N. / Tian, G. ...Johansson, P. / Albert, J.S. / Spadola, L. / Akerud, T. / Back, E. / Hillertz, P. / Horsefeld, R. / Scott, C. / Spear, N. / Tian, G. / Tigerstrom, A. / Aharony, D. / Geschwindner, S.
CitationJournal: To be Published
Title: Identification and Structural Characterization of Pde10 Fragment Inhibitors
Authors: Johansson, P. / Albert, J.S. / Spadola, L. / Akerud, T. / Back, E. / Hillertz, P. / Horsefeld, R. / Scott, C. / Spear, N. / Tian, G. / Tigerstrom, A. / Aharony, D. / Geschwindner, S.
History
DepositionFeb 16, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 6, 2013Provider: repository / Type: Initial release

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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
D: CAMP AND CAMP-INHIBITED CGMP 3', 5'-CYCLIC PHOSPHODIESTERASE 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,4218
Polymers75,8692
Non-polymers5526
Water1,45981
1
A: CAMP AND CAMP-INHIBITED CGMP 3', 5'-CYCLIC PHOSPHODIESTERASE 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2114
Polymers37,9351
Non-polymers2763
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
D: CAMP AND CAMP-INHIBITED CGMP 3', 5'-CYCLIC PHOSPHODIESTERASE 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2114
Polymers37,9351
Non-polymers2763
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.609, 81.466, 157.198
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21D

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1115A448 - 769
2115D448 - 769

NCS oper: (Code: given
Matrix: (-0.174, -0.943, -0.284), (0.981, -0.14, -0.135), (0.088, -0.302, 0.949)
Vector: -0.0422, -0.77611, 0.0522)

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Components

#1: Protein CAMP AND CAMP-INHIBITED CGMP 3', 5'-CYCLIC PHOSPHODIESTERASE 10A / PDE10 / PHOSPHODIESTERASE 10A


Mass: 37934.602 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN, RESIDUES 439-764
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / 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-F07 / THIENO[3,2-C][1,6]NAPHTHYRIDINE


Mass: 186.233 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H6N2S
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 81 / 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: 2.16 Å3/Da / Density % sol: 43.15 % / Description: NONE
Crystal growpH: 7
Details: 13-18% PEG3350, 4-10 MM TCEP, 100 MM HEPES PH 7.5 AND 200MM MGCL2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.96
DetectorType: ADSC CCD / Detector: CCD / Date: Sep 5, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96 Å / Relative weight: 1
ReflectionResolution: 2.3→47.31 Å / Num. obs: 25159 / % possible obs: 86.5 % / Observed criterion σ(I): 2 / Redundancy: 3.7 % / Rmerge(I) obs: 0.13 / Net I/σ(I): 6.9
Reflection shellResolution: 2.3→2.36 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.88 / Mean I/σ(I) obs: 1.7 / % possible all: 72.3

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Processing

Software
NameVersionClassification
REFMAC5.5.0102refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→50 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.892 / SU B: 10.339 / SU ML: 0.248 / Cross valid method: THROUGHOUT / ESU R: 1.108 / ESU R Free: 0.337 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.27699 1199 5 %RANDOM
Rwork0.21275 ---
obs0.21602 22611 81.67 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 47.045 Å2
Baniso -1Baniso -2Baniso -3
1-2.34 Å20 Å20 Å2
2---2.49 Å20 Å2
3---0.15 Å2
Refinement stepCycle: LAST / Resolution: 2.3→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5205 0 30 81 5316
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0225396
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3821.9537314
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3245647
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.6324.094254
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.66115952
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.3981529
X-RAY DIFFRACTIONr_chiral_restr0.0940.2798
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0214129
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5481.53227
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.03525235
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.45132169
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.3394.52079
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Dom-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1A1272medium positional0.250.5
2D1272medium positional0.250.5
1A1298loose positional0.545
2D1298loose positional0.545
1A1272medium thermal0.772
2D1272medium thermal0.772
1A1298loose thermal0.9110
2D1298loose thermal0.9110
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.436 68 -
Rwork0.333 1253 -
obs--61.67 %

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