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- PDB-7qq4: Discovery of Lu AF11167, a Phosphodiesterase 10A inhibitor clinic... -

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Basic information

Entry
Database: PDB / ID: 7qq4
TitleDiscovery of Lu AF11167, a Phosphodiesterase 10A inhibitor clinical candidate
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE / Phosphodiesterase / PDE / PDE10A / schizophrenia / basal ganglia disorders
Function / homology
Function and homology information


3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cAMP catabolic process / regulation of cAMP/PKA signal transduction / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / cGMP binding ...3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cAMP catabolic process / regulation of cAMP/PKA signal transduction / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / : / cAMP binding / G alpha (s) signalling events / glutamatergic synapse / 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 / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / GAF-like domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-EIK / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsLeonard, P.M. / Langgard, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Discovery of Lu AF11167, a Phosphodiesterase 10A inhibitor clinical candidate
Authors: Kehler, J. / Kilburn, J.P. / Langgard, M. / Christoffersen, C.T. / Ritzen, A. / Marigo, M. / Jessing, M. / Bundgaard, C. / Puschl, A. / Feigin, K. / Nielsen, J.
History
DepositionJan 6, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 19, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)80,0978
Polymers79,2532
Non-polymers8446
Water1,44180
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0494
Polymers39,6271
Non-polymers4223
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0494
Polymers39,6271
Non-polymers4223
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)49.357, 81.078, 159.482
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 39626.531 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase
#2: Chemical ChemComp-EIK / 5,8-dimethyl-2-[2-(1-methyl-4-phenyl-imidazol-2-yl)ethyl]-[1,2,4]triazolo[1,5-a]pyrazine


Mass: 332.402 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H20N6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 80 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.01 Å3/Da / Density % sol: 38.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.9
Details: 0.1 M Tris-HCl, 8 % w/v PEG 3350, 25 mM CaCl2, 1mM THP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Apr 7, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.45→79.74 Å / Num. obs: 22786 / % possible obs: 94.9 % / Redundancy: 2.8 % / Rmerge(I) obs: 0.086 / Net I/σ(I): 8
Reflection shellResolution: 2.45→2.514 Å / Rmerge(I) obs: 0.474 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 1558

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1t9r

1t9r


Resolution: 2.45→79.74 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.898 / Cross valid method: THROUGHOUT / ESU R: 1.185 / ESU R Free: 0.346 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27926 1173 5.2 %RANDOM
Rwork0.23026 ---
obs0.23275 21555 93.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 34.078 Å2
Baniso -1Baniso -2Baniso -3
1-1.21 Å20 Å20 Å2
2---2.82 Å20 Å2
3---1.61 Å2
Refinement stepCycle: 1 / Resolution: 2.45→79.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4943 0 54 80 5077
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0215123
X-RAY DIFFRACTIONr_bond_other_d00.023362
X-RAY DIFFRACTIONr_angle_refined_deg1.0181.9586964
X-RAY DIFFRACTIONr_angle_other_deg4.1838202
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.4315622
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.57524.138232
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.42515841
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.5941523
X-RAY DIFFRACTIONr_chiral_restr0.0460.2769
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0215683
X-RAY DIFFRACTIONr_gen_planes_other0.0040.021050
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_it0.3231.53114
X-RAY DIFFRACTIONr_mcbond_other01.51250
X-RAY DIFFRACTIONr_mcangle_it0.59125020
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.42832009
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it0.7324.51944
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
LS refinement shellResolution: 2.45→2.514 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.363 76 -
Rwork0.337 1558 -
obs--93.42 %

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