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- PDB-8di4: Discovery of MK-8189, a highly potent and selective PDE10A inhibi... -

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Basic information

Entry
Database: PDB / ID: 8di4
TitleDiscovery of MK-8189, a highly potent and selective PDE10A inhibitor for the treatment of schizophrenia
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PDE10A / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
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-S9I / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.016 Å
AuthorsHayes, R.P. / Yan, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia.
Authors: Layton, M.E. / Kern, J.C. / Hartingh, T.J. / Shipe, W.D. / Raheem, I. / Kandebo, M. / Hayes, R.P. / Huszar, S. / Eddins, D. / Ma, B. / Fuerst, J. / Wollenberg, G.K. / Li, J. / Fritzen, J. / ...Authors: Layton, M.E. / Kern, J.C. / Hartingh, T.J. / Shipe, W.D. / Raheem, I. / Kandebo, M. / Hayes, R.P. / Huszar, S. / Eddins, D. / Ma, B. / Fuerst, J. / Wollenberg, G.K. / Li, J. / Fritzen, J. / McGaughey, G.B. / Uslaner, J.M. / Smith, S.M. / Coleman, P.J. / Cox, C.D.
History
DepositionJun 28, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 8, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
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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)80,1578
Polymers79,2132
Non-polymers9446
Water1,892105
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0794
Polymers39,6061
Non-polymers4723
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)40,0794
Polymers39,6061
Non-polymers4723
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)49.730, 81.360, 157.749
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 39606.430 Da / Num. of mol.: 2 / Fragment: catalytic domain residues 439-779
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.: 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-S9I / 2-methyl-6-{[(1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrimidin-4-amine


Mass: 382.483 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H22N6OS / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 105 / 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: 38.94 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 18% PEG3350, 0.2M MgCl2, 10mM 2-Mercaptoethanol, 0.1M HEPES, pH7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 24, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.016→78.875 Å / Num. obs: 41974 / % possible obs: 97.3 % / Redundancy: 6.4 % / Biso Wilson estimate: 41.64 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.046 / Rrim(I) all: 0.051 / Net I/σ(I): 19.6
Reflection shellResolution: 2.016→2.051 Å / Rmerge(I) obs: 0.811 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 14248 / CC1/2: 0.894 / Rrim(I) all: 0.88

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Processing

Software
NameVersionClassification
autoPROC1.1.7data scaling
BUSTER2.11.8 (16-JUL-2021)refinement
PDB_EXTRACT3.27data extraction
autoPROC1.1.7data reduction
autoBUSTER1.1.7phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5c2h

5c2h


Resolution: 2.016→78.87 Å / Cor.coef. Fo:Fc: 0.909 / Cor.coef. Fo:Fc free: 0.881 / SU R Cruickshank DPI: 0.256 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.256 / SU Rfree Blow DPI: 0.211 / SU Rfree Cruickshank DPI: 0.212
RfactorNum. reflection% reflectionSelection details
Rfree0.2946 2102 5.01 %RANDOM
Rwork0.2499 ---
obs0.2521 41973 97.2 %-
Displacement parametersBiso max: 89.82 Å2 / Biso mean: 48.45 Å2 / Biso min: 20.39 Å2
Baniso -1Baniso -2Baniso -3
1--20.5169 Å20 Å20 Å2
2--15.3043 Å20 Å2
3---5.2126 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: final / Resolution: 2.016→78.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5151 0 58 105 5314
Biso mean--35.66 41.73 -
Num. residues----642
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1841SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes931HARMONIC5
X-RAY DIFFRACTIONt_it5341HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion696SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4613SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5341HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg7245HARMONIC20.89
X-RAY DIFFRACTIONt_omega_torsion2.71
X-RAY DIFFRACTIONt_other_torsion17.5
LS refinement shellResolution: 2.02→2.03 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.4411 47 5.6 %
Rwork0.3649 793 -
all0.369 840 -
obs--97.84 %

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