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- PDB-5b4k: Crystal structure of the catalytic domain of human PDE10A complex... -

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Basic information

Entry
Database: PDB / ID: 5b4k
TitleCrystal structure of the catalytic domain of human PDE10A complexed with N-(4-((5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)oxy)phenyl)-1H-benzimidazol-2-amine
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / 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 receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cAMP catabolic process / regulation of cAMP/PKA signal transduction / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 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 / cAMP catabolic process / regulation of cAMP/PKA signal transduction / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / : / cAMP binding / G alpha (s) signalling events / glutamatergic synapse / 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-6DT / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsOki, H. / Zama, Y.
CitationJournal: Bioorg.Med.Chem. / Year: 2016
Title: Design and synthesis of potent and selective pyridazin-4(1H)-one-based PDE10A inhibitors interacting with Tyr683 in the PDE10A selectivity pocket
Authors: Yoshikawa, M. / Hitaka, T. / Hasui, T. / Fushimi, M. / Kunitomo, J. / Kokubo, H. / Oki, H. / Nakashima, K. / Taniguchi, T.
History
DepositionApr 5, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 29, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 3, 2016Group: Database references
Revision 1.2Nov 8, 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 / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / pdbx_struct_oper_list / struct_conn
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _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 / _pdbx_struct_oper_list.symmetry_operation / _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)78,6718
Polymers77,7792
Non-polymers8926
Water2,684149
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,3364
Polymers38,8901
Non-polymers4463
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-34 kcal/mol
Surface area14670 Å2
MethodPISA
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,3364
Polymers38,8901
Non-polymers4463
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-33 kcal/mol
Surface area14500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.734, 81.683, 161.654
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: 38889.586 Da / Num. of mol.: 2 / Fragment: catalytic domain, UNP residues 442-779
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Plasmid: pET15b / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-6DT / N-(4-((5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)oxy)phenyl)-1H-benzimidazol-2-amine


Mass: 356.381 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H16N6O
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 149 / 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: 41.73 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 100 mM HEPES pH 7.6, 100 mM magnesium chloride hexahydrate, 24.182% PEG 3350
PH range: 7.5-8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 9, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→80.83 Å / Num. obs: 13970 / % possible obs: 90.9 % / Redundancy: 6 % / Net I/σ(I): 18.3
Reflection shellResolution: 2.9→2.97 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
HKL-2000data reduction
MOLREPphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3WYM

3wym


Resolution: 2.9→80.83 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.903 / SU B: 35.48 / SU ML: 0.335 / Cross valid method: THROUGHOUT / ESU R Free: 0.505
RfactorNum. reflection% reflectionSelection details
Rfree0.26051 681 4.9 %RANDOM
Rwork0.17684 ---
obs0.1808 13191 90.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 56.224 Å2
Baniso -1Baniso -2Baniso -3
1-3.54 Å2-0 Å20 Å2
2---5.13 Å20 Å2
3---1.59 Å2
Refinement stepCycle: 1 / Resolution: 2.9→80.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5129 0 58 149 5336
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0195319
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.9141.9617206
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.0225629
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.26624.104251
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.0815934
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.1731528
X-RAY DIFFRACTIONr_chiral_restr0.0590.2779
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0214134
X-RAY DIFFRACTIONr_gen_planes_other
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_it2.8366.582522
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.55411.0963149
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.7496.9892797
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined8.21845.128521
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.291 36 -
Rwork0.263 552 -
obs--53.8 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.37630.12540.11840.88280.02220.3928-0.0250.01650.00730.07560.0228-0.0461-0.04580.00020.00220.02680.0034-0.0170.0217-0.0040.013616.34832.3981-12.9771
20.14490.05070.05390.9932-0.21390.79660.0155-0.00610.0468-0.0153-0.0895-0.02210.07640.01110.0740.01390.00130.01150.03580.00430.02047.2982-34.2611-26.3483
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A445 - 759
2X-RAY DIFFRACTION1A1001 - 1003
3X-RAY DIFFRACTION2B445 - 760
4X-RAY DIFFRACTION2B1001 - 1003

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