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

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Basic information

Entry
Database: PDB / ID: 7qpm
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 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 ...3',5'-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
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 ...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 / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain
Similarity search - Domain/homology
Chem-EEI / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 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 5, 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)80,1318
Polymers79,2532
Non-polymers8786
Water4,216234
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0664
Polymers39,6271
Non-polymers4393
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)40,0664
Polymers39,6271
Non-polymers4393
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)49.260, 81.660, 159.660
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-EEI / 5,7-dimethyl-2-[(1-methyl-4-phenyl-imidazol-2-yl)sulfanylmethyl]imidazo[1,2-a]pyrimidine


Mass: 349.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H19N5S / 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.: 234 / 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: 2.03 Å3/Da / Density % sol: 39.29 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 0.1M Hepes, 18% PEG3350

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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: Jan 10, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.4→39.56 Å / Num. obs: 25490 / % possible obs: 98.6 % / Redundancy: 3.1 % / Rmerge(I) obs: 0.124 / Net I/σ(I): 13.2
Reflection shellResolution: 2.4→2.49 Å / Rmerge(I) obs: 0.552 / Mean I/σ(I) obs: 3.7 / Num. unique obs: 2650

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1t9r

1t9r


Resolution: 2.4→39.56 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.903 / SU B: 8.724 / SU ML: 0.201 / Cross valid method: THROUGHOUT / ESU R: 0.591 / ESU R Free: 0.288 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24952 1304 5.1 %RANDOM
Rwork0.1741 ---
obs0.17785 24166 97.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 38.644 Å2
Baniso -1Baniso -2Baniso -3
1-0.68 Å20 Å2-0 Å2
2---0.48 Å20 Å2
3----0.2 Å2
Refinement stepCycle: 1 / Resolution: 2.4→39.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5053 0 54 234 5341
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0135233
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174748
X-RAY DIFFRACTIONr_angle_refined_deg1.4791.6387098
X-RAY DIFFRACTIONr_angle_other_deg1.3011.56711012
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.035628
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.54622.612268
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.94615896
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2721527
X-RAY DIFFRACTIONr_chiral_restr0.0730.2676
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025792
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021111
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_it3.2714.0612518
X-RAY DIFFRACTIONr_mcbond_other3.2644.062517
X-RAY DIFFRACTIONr_mcangle_it4.5986.0833144
X-RAY DIFFRACTIONr_mcangle_other4.5986.0843145
X-RAY DIFFRACTIONr_scbond_it3.64.2932715
X-RAY DIFFRACTIONr_scbond_other3.6014.2942714
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.3846.313955
X-RAY DIFFRACTIONr_long_range_B_refined7.94575.78822935
X-RAY DIFFRACTIONr_long_range_B_other7.92675.84922805
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.304 103 -
Rwork0.232 1749 -
obs--97.47 %

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