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- PDB-6ijh: Crystal structure of PDE10 in complex with inhibitor AF-399/14387019 -

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Basic information

Entry
Database: PDB / ID: 6ijh
TitleCrystal structure of PDE10 in complex with inhibitor AF-399/14387019
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/INHIBITOR / 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
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 / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-AEO / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsHuang, Y.Y. / Yu, Y.F. / Zhang, C. / Wu, D. / Wu, Y. / Luo, H.B.
Funding support China, 4items
OrganizationGrant numberCountry
National Natural Science Foundation of China81522041 China
National Natural Science Foundation of China21572279 China
National Natural Science Foundation of China81602955 China
National Natural Science Foundation of China21402243 China
CitationJournal: J. Med. Chem. / Year: 2019
Title: Validation of Phosphodiesterase-10 as a Novel Target for Pulmonary Arterial Hypertension via Highly Selective and Subnanomolar Inhibitors.
Authors: Huang, Y.Y. / Yu, Y.F. / Zhang, C. / Chen, Y. / Zhou, Q. / Li, Z. / Zhou, S. / Li, Z. / Guo, L. / Wu, D. / Wu, Y. / Luo, H.B.
History
DepositionOct 10, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 10, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 22, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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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)79,9058
Polymers78,9252
Non-polymers9806
Water1,13563
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9524
Polymers39,4621
Non-polymers4903
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-34 kcal/mol
Surface area14710 Å2
MethodPISA
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9524
Polymers39,4621
Non-polymers4903
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-34 kcal/mol
Surface area14670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.342, 81.693, 159.816
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: 39462.301 Da / Num. of mol.: 2 / Fragment: UNP residues 439-779
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
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-AEO / 2-[2-(4-phenyl-5-sulfanylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]-1H-benzo[de]isoquinoline-1,3(2H)-dione


Mass: 400.453 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C22H16N4O2S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 63 / 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: 2.11 Å3/Da / Density % sol: 41.59 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1M Hepes (pH 7.5), 0.2M MgCl2, 18% PEG 3350, 50mM 2-mercaptoethanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: OXFORD DIFFRACTION ENHANCE ULTRA / Wavelength: 1.5418 Å
DetectorType: OXFORD ONYX CCD / Detector: CCD / Date: Jan 20, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.6→79.91 Å / Num. obs: 20517 / % possible obs: 99.81 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.093 / Net I/σ(I): 14.8
Reflection shellResolution: 2.6→2.7 Å / Rmerge(I) obs: 0.257 / Num. unique obs: 4255

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
CrysalisPro38.41data reduction
CrysalisPro38.41data scaling
PHASER1.1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OUP

2oup


Resolution: 2.6→79.91 Å / Cor.coef. Fo:Fc: 0.889 / Cor.coef. Fo:Fc free: 0.807 / SU B: 19.274 / SU ML: 0.405 / Cross valid method: THROUGHOUT / ESU R Free: 0.433 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.31214 1012 4.9 %RANDOM
Rwork0.24019 ---
obs0.24375 19505 99.63 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 36.758 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0.03 Å2-0 Å2
3----0.03 Å2
Refinement stepCycle: 1 / Resolution: 2.6→79.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5221 0 62 63 5346
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0195416
X-RAY DIFFRACTIONr_bond_other_d0.0010.024916
X-RAY DIFFRACTIONr_angle_refined_deg1.1331.9367339
X-RAY DIFFRACTIONr_angle_other_deg0.91311429
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4835642
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.6624.087252
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.18915953
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.8821528
X-RAY DIFFRACTIONr_chiral_restr0.0610.2796
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.026260
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021124
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_it0.9993.7562574
X-RAY DIFFRACTIONr_mcbond_other13.7552573
X-RAY DIFFRACTIONr_mcangle_it1.7455.6293214
X-RAY DIFFRACTIONr_mcangle_other1.7445.633215
X-RAY DIFFRACTIONr_scbond_it0.7733.8172842
X-RAY DIFFRACTIONr_scbond_other0.7733.8172843
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.355.694126
X-RAY DIFFRACTIONr_long_range_B_refined3.77743.4516223
X-RAY DIFFRACTIONr_long_range_B_other3.77743.4556224
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.6→2.668 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.363 70 -
Rwork0.319 1365 -
obs--98.09 %

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