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- PDB-5znl: Crystal structure of PDE10A catalytic domain complexed with LHB-6 -

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Basic information

Entry
Database: PDB / ID: 5znl
TitleCrystal structure of PDE10A catalytic domain complexed with LHB-6
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE / PDE10A inhibitor
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 / cGMP effects / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway ...3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cGMP effects / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 3',5'-cyclic-AMP phosphodiesterase activity / negative regulation of cAMP/PKA signal transduction / cAMP binding / G alpha (s) signalling events / glutamatergic synapse / signal transduction / 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-9G6 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsLi, Z. / Huang, Y. / Zhan, C.G. / Luo, H.B.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China81522041, 81373258, 21572279, 21402243 China
CitationJournal: J. Med. Chem. / Year: 2019
Title: Absolute Binding Free Energy Calculation and Design of a Subnanomolar Inhibitor of Phosphodiesterase-10.
Authors: Li, Z. / Huang, Y. / Wu, Y. / Chen, J. / Wu, D. / Zhan, C.G. / Luo, H.B.
History
DepositionApr 9, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 20, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 13, 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.title / _citation_author.name
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 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_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

Downloads & links

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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)75,8978
Polymers74,8422
Non-polymers1,0546
Water1,44180
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,9484
Polymers37,4211
Non-polymers5273
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area230 Å2
ΔGint-48 kcal/mol
Surface area13980 Å2
MethodPISA
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,9484
Polymers37,4211
Non-polymers5273
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area230 Å2
ΔGint-48 kcal/mol
Surface area14070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.151, 81.328, 158.207
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: 37421.125 Da / Num. of mol.: 2
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: isolated from a natural source / Formula: Mg
#4: Chemical ChemComp-9G6 / N-[2-(7-methoxy-4-morpholin-4-yl-quinazolin-6-yl)oxyethyl]-1,3-benzothiazol-2-amine


Mass: 437.515 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H23N5O3S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 80 / 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: 2.12 Å3/Da / Density % sol: 41.77 %
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
Diffraction sourceSource: SEALED TUBE / Type: OXFORD DIFFRACTION ENHANCE ULTRA / Wavelength: 1.5418 Å
DetectorType: OXFORD ONYX CCD / Detector: CCD / Date: Feb 2, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.8→79.1 Å / Num. obs: 15928 / % possible obs: 97.86 % / Redundancy: 4.6 % / Rmerge(I) obs: 0.063 / Net I/σ(I): 11.7
Reflection shellResolution: 2.8→2.9 Å / Rmerge(I) obs: 0.209 / Num. unique obs: 5332

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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: 1OUP

1oup


Resolution: 2.8→79.1 Å / Cor.coef. Fo:Fc: 0.887 / Cor.coef. Fo:Fc free: 0.8 / SU B: 23.416 / SU ML: 0.45 / Cross valid method: THROUGHOUT / ESU R Free: 0.513 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.30662 776 4.9 %RANDOM
Rwork0.23435 ---
obs0.23798 15129 97.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 33.328 Å2
Baniso -1Baniso -2Baniso -3
1-0.04 Å20 Å20 Å2
2--0.06 Å2-0 Å2
3----0.1 Å2
Refinement stepCycle: 1 / Resolution: 2.8→79.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5003 0 66 80 5149
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0195197
X-RAY DIFFRACTIONr_bond_other_d0.0010.024665
X-RAY DIFFRACTIONr_angle_refined_deg1.1751.9397055
X-RAY DIFFRACTIONr_angle_other_deg0.929310809
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7575630
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.25523.939231
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.18415861
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2771525
X-RAY DIFFRACTIONr_chiral_restr0.0610.2777
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0215971
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021078
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_it1.0973.5322526
X-RAY DIFFRACTIONr_mcbond_other1.0953.5322525
X-RAY DIFFRACTIONr_mcangle_it1.9345.2933154
X-RAY DIFFRACTIONr_mcangle_other1.9345.2943155
X-RAY DIFFRACTIONr_scbond_it0.7013.4432671
X-RAY DIFFRACTIONr_scbond_other0.73.4432672
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.2425.1523902
X-RAY DIFFRACTIONr_long_range_B_refined3.7640.5796065
X-RAY DIFFRACTIONr_long_range_B_other3.75940.5786066
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.8→2.873 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.463 64 -
Rwork0.306 1099 -
obs--98.39 %

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