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- PDB-3sni: Highly Potent, Selective, and Orally Active Phosphodiestarase 10A... -

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Basic information

Entry
Database: PDB / ID: 3sni
TitleHighly Potent, Selective, and Orally Active Phosphodiestarase 10A Inhibitors
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Hydrolase / Hydrolase inhibitor / Zn Binding / 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
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-546 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsMalamas, M.S. / Ni, Y. / Erdei, J. / Stange, H. / Schindler, R. / Lankau, H.-J. / Grunwald, C. / Fan, K.Y. / Parris, K.D. / Langen, B. ...Malamas, M.S. / Ni, Y. / Erdei, J. / Stange, H. / Schindler, R. / Lankau, H.-J. / Grunwald, C. / Fan, K.Y. / Parris, K.D. / Langen, B. / Egerland, U. / Hage, T. / Marquis, K.L. / Grauer, S. / Brennan, J. / Navarra, R. / Graf, R. / Harrison, B.L. / Robichaud, A. / Kronbach, T. / Pangalos, M. / Hofgen, N. / Brandon, N.J.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors.
Authors: Malamas, M.S. / Ni, Y. / Erdei, J. / Stange, H. / Schindler, R. / Lankau, H.J. / Grunwald, C. / Fan, K.Y. / Parris, K. / Langen, B. / Egerland, U. / Hage, T. / Marquis, K.L. / Grauer, S. / ...Authors: Malamas, M.S. / Ni, Y. / Erdei, J. / Stange, H. / Schindler, R. / Lankau, H.J. / Grunwald, C. / Fan, K.Y. / Parris, K. / Langen, B. / Egerland, U. / Hage, T. / Marquis, K.L. / Grauer, S. / Brennan, J. / Navarra, R. / Graf, R. / Harrison, B.L. / Robichaud, A. / Kronbach, T. / Pangalos, M.N. / Hoefgen, N. / Brandon, N.J.
History
DepositionJun 29, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 26, 2011Provider: repository / Type: Initial release
Revision 1.1Nov 16, 2011Group: Database references
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
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_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_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 / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_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)80,10210
Polymers79,2132
Non-polymers8898
Water4,702261
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0515
Polymers39,6061
Non-polymers4454
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0515
Polymers39,6061
Non-polymers4454
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.245, 81.337, 157.415
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 39606.430 Da / Num. of mol.: 2 / Fragment: Catalytic Domain, UNP 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

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Non-polymers , 5 types, 269 molecules

#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-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-546 / 2-methoxy-6,7-dimethyl-9-(4-methylpyridin-3-yl)imidazo[1,5-a]pyrido[3,2-e]pyrazine


Mass: 319.360 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H17N5O
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 261 / 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: 2.07 Å3/Da / Density % sol: 40.6 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.1
Details: 12-18% PEG 3350, 100 mM MES pH 7.1, 3-6% methanol, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Aug 4, 2008
RadiationMonochromator: Si 111. Rosenbaum-Rock double-crystal monochromator: liquid nitrogen cooled; sagitally focusing 2nd crystal, Rosenbaum-Rock vertical focusing mirror
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→48.74 Å / Num. all: 53114 / Num. obs: 31778 / % possible obs: 59.8 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1
Reflection shell
Resolution (Å)Diffraction-ID% possible all
1.9-1.97111.8
1.97-2.05117
2.05-2.14127.4
2.14-2.25136.4
2.25-2.39151
2.39-2.58167.2
2.58-2.84188.1
2.84-3.25199.5
3.25-4.09198.5
4.09-50196.1

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Processing

Software
NameVersionClassification
MAR345data collection
PHASERphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→48.74 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.868 / SU B: 6.715 / SU ML: 0.195 / Cross valid method: THROUGHOUT / σ(F): 1 / ESU R Free: 0.311 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.31875 1589 5 %RANDOM
Rwork0.24724 ---
all0.251 31778 --
obs0.25089 30140 59.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 36.907 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2---0.02 Å20 Å2
3---0.02 Å2
Refinement stepCycle: LAST / Resolution: 1.9→48.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5120 0 54 261 5435
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0225335
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0081.9597234
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8445637
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.69624.137249
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.84415943
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.1411528
X-RAY DIFFRACTIONr_chiral_restr0.0690.2787
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.024025
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1810.22836
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.2920.23712
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1290.2325
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined0.140.27
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.170.265
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2690.219
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.3711.53295
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.65825156
X-RAY DIFFRACTIONr_scbond_it0.62732465
X-RAY DIFFRACTIONr_scangle_it0.9854.52078
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.9→1.945 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.516 29 -
Rwork0.436 411 -
obs--11.51 %

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