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- PDB-6ko0: The crystal structue of PDE10A complexed with 1i -

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Basic information

Entry
Database: PDB / ID: 6ko0
TitleThe crystal structue of PDE10A complexed with 1i
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE / PDE10A inhibitor
Function / homology
Function and homology information


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 / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity ...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 / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / 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 / GAF domain / 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. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 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. / 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-DKU / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.60002905998 Å
AuthorsHuang, Y.-Y. / Yu, Y.F. / Zhang, C. / Guo, L. / Wu, D. / Luo, H.-B.
Funding support China, 5items
OrganizationGrant numberCountry
National Natural Science Foundation of China81872727 China
National Natural Science Foundation of China81602955 China
National Natural Science Foundation of China21702238 China
National Natural Science Foundation of China21708052 China
National Natural Science Foundation of China81703341 China
CitationJournal: Acs Chem Neurosci / Year: 2020
Title: Discovery and Optimization of Chromone Derivatives as Novel Selective Phosphodiesterase 10 Inhibitors.
Authors: Yu, Y.F. / Zhang, C. / Huang, Y.Y. / Zhang, S. / Zhou, Q. / Li, X. / Lai, Z. / Li, Z. / Gao, Y. / Wu, Y. / Guo, L. / Wu, D. / Luo, H.B.
History
DepositionAug 7, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 1, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 15, 2020Group: 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 / 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

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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)75,5248
Polymers74,5842
Non-polymers9406
Water3,531196
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7624
Polymers37,2921
Non-polymers4703
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-32 kcal/mol
Surface area14220 Å2
MethodPISA
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7624
Polymers37,2921
Non-polymers4703
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-34 kcal/mol
Surface area14440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.213, 81.535, 161.375
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A


Mass: 37292.012 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-DKU / 3-[2-(5-methyl-1-phenyl-benzimidazol-2-yl)ethyl]chromen-4-one


Mass: 380.439 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H20N2O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: isolated from a natural source / 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 / Water


Mass: 18.015 Da / Num. of mol.: 196 / 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: 2.22 Å3/Da / Density % sol: 44.48 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1 M Hepes (pH 7.5), 0.2 M MgCl2, 18% PEG 3350, 50 mM 2-mercaptoethanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: OXFORD DIFFRACTION NOVA / Wavelength: 1.5418 Å
DetectorType: OXFORD ONYX CCD / Detector: CCD / Date: Jan 24, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.6→24.78 Å / Num. obs: 20094 / % possible obs: 97 % / Redundancy: 3.8 % / Biso Wilson estimate: 28.8784149391 Å2 / Rmerge(I) obs: 0.076 / Net I/σ(I): 18.3
Reflection shellResolution: 2.6→2.69 Å / Redundancy: 4 % / Rmerge(I) obs: 0.218 / Mean I/σ(I) obs: 5.1 / Num. unique obs: 2015 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.10_2155refinement
CrysalisPro38.42data reduction
CrysalisPro38.42data scaling
PHASER1.1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OUP

2oup


Resolution: 2.60002905998→24.7765700799 Å / SU ML: 0.555453505042 / Cross valid method: FREE R-VALUE / σ(F): 1.99181202448 / Phase error: 32.6313708614
RfactorNum. reflection% reflection
Rfree0.327303176933 966 4.80740519558 %
Rwork0.214819538269 --
obs0.220104788871 20094 97.1945438715 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 30.0466415313 Å2
Refinement stepCycle: LAST / Resolution: 2.60002905998→24.7765700799 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5109 0 62 196 5367
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.009340190714535301
X-RAY DIFFRACTIONf_angle_d1.117644383037182
X-RAY DIFFRACTIONf_chiral_restr0.054983819975780
X-RAY DIFFRACTIONf_plane_restr0.00645189982966979
X-RAY DIFFRACTIONf_dihedral_angle_d15.43206549363200
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.61-2.73690.4571804288871400.3038735281222755X-RAY DIFFRACTION99.8964803313
2.7369-2.90820.369430405181490.2868159414552746X-RAY DIFFRACTION99.7931747673
2.9082-3.13230.4084514809171360.2638674980682739X-RAY DIFFRACTION99.6533795494
3.1323-3.44680.3417505155781370.2343852735222758X-RAY DIFFRACTION98.9405331511
3.4468-3.94380.3079201452981400.201405883572726X-RAY DIFFRACTION97.3505434783
3.9438-4.96220.3090354260461250.1767567383822697X-RAY DIFFRACTION94.0980326776
4.9622-24.70.2379742250411390.1573902562312707X-RAY DIFFRACTION91.2179487179

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