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- PDB-4d09: PDE2a catalytic domain in complex with a brain penetrant inhibitor -

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Basic information

Entry
Database: PDB / ID: 4d09
TitlePDE2a catalytic domain in complex with a brain penetrant inhibitor
ComponentsCGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE
KeywordsHYDROLASE / CYCLIC NUCLEOTIDE PHOSPHODIESTERASES / TYPE 2 / TYPE 4 / DISEASE MODELS / ANIMAL / DRUG EVALUATION / PRECLINICAL / PHOSPHODIESTERASE 2 INHIBITORS / PHOSPHODIESTERASE INHIBITORS / PROTEIN BINDING / STRUCTURE-ACTIVITY RELATIONSHIP
Function / homology
Function and homology information


regulation of cGMP-mediated signaling / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / cellular response to macrophage colony-stimulating factor stimulus / cellular response to cGMP / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of vascular permeability / heart valve development / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of vascular permeability / establishment of endothelial barrier ...regulation of cGMP-mediated signaling / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / cellular response to macrophage colony-stimulating factor stimulus / cellular response to cGMP / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of vascular permeability / heart valve development / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of vascular permeability / establishment of endothelial barrier / negative regulation of cAMP-mediated signaling / regulation of mitochondrion organization / aorta development / ventricular septum development / cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP-mediated signaling / TPR domain binding / cGMP catabolic process / phosphate ion binding / cGMP effects / monocyte differentiation / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / regulation of cAMP-mediated signaling / cAMP binding / cellular response to cAMP / cellular response to transforming growth factor beta stimulus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cAMP-mediated signaling / synaptic membrane / positive regulation of inflammatory response / cellular response to mechanical stimulus / cellular response to xenobiotic stimulus / presynaptic membrane / G alpha (s) signalling events / mitochondrial outer membrane / mitochondrial inner membrane / mitochondrial matrix / positive regulation of gene expression / perinuclear region of cytoplasm / Golgi apparatus / negative regulation of transcription by RNA polymerase II / magnesium ion binding / endoplasmic reticulum / protein homodimerization activity / zinc ion binding / identical protein binding / nucleus / plasma membrane / cytoplasm / 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-788 / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsBuijnsters, P. / Andres, J.I. / DeAngelis, M. / Langlois, X. / Rombouts, F. / Sanderson, W. / Tresadern, G. / Trabanco, A. / VanHoof, G. / VanRoosbroeck, Y.
CitationJournal: Acs Med.Chem.Lett. / Year: 2014
Title: Structure-Based Design of a Potent, Selective, and Brain Penetrating Pde2 Inhibitor with Demonstrated Target Engagement.
Authors: Buijnsters, P. / De Angelis, M. / Langlois, X. / Rombouts, F.J.R. / Sanderson, W. / Tresadern, G. / Ritchie, A. / Trabanco, A.A. / Vanhoof, G. / Roosbroeck, Y.V. / Andres, J.
History
DepositionApr 24, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 6, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 24, 2014Group: Database references
Revision 1.2Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.3May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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.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_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_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_conn.ptnr2_label_seq_id / _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: CGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE
B: CGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE
C: CGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE
D: CGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)167,66216
Polymers165,7304
Non-polymers1,93312
Water4,774265
1
A: CGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,9164
Polymers41,4321
Non-polymers4833
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: CGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,9164
Polymers41,4321
Non-polymers4833
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: CGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,9164
Polymers41,4321
Non-polymers4833
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: CGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,9164
Polymers41,4321
Non-polymers4833
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)56.140, 73.430, 91.620
Angle α, β, γ (deg.)109.37, 91.82, 91.05
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
CGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE / CYCLIC GMP-STIMULATED PHOSPHODIESTERASE / CGS-PDE / CGSPDE / PDE2A


Mass: 41432.375 Da / Num. of mol.: 4 / Fragment: CATALYTIC DOMAIN, RESIDUES 578-921
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: O00408, 3',5'-cyclic-nucleotide phosphodiesterase
#2: Chemical
ChemComp-788 / N-benzyl-4-methyl-1-phenyl[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide


Mass: 393.441 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H19N5O
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 265 / 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: 2.3 Å3/Da / Density % sol: 46.4 % / Description: NONE
Crystal growpH: 7
Details: 0.2 M MGCL2, 0.1 M TRIS-HCL PH 7.0 AND 20 % PEG 3350 IN PRESENCE OF 1 MM LIGAND

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Jun 8, 2009 / Details: VARIAMAXHF
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.5→30 Å / Num. obs: 44706 / % possible obs: 93.7 % / Observed criterion σ(I): 1.8 / Redundancy: 1.9 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 5.8
Reflection shellResolution: 2.5→2.6 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 1.8 / % possible all: 85.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0071refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: INTERNAL PDE2A MODEL

Resolution: 2.5→19.77 Å / Cor.coef. Fo:Fc: 0.924 / Cor.coef. Fo:Fc free: 0.858 / SU B: 13.952 / SU ML: 0.303 / Cross valid method: THROUGHOUT / ESU R Free: 0.369 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27746 2266 5.1 %RANDOM
Rwork0.20642 ---
obs0.21004 42432 93.67 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 30.798 Å2
Baniso -1Baniso -2Baniso -3
1-0.1 Å2-0.1 Å2-0.11 Å2
2---0.19 Å2-0.02 Å2
3---0.09 Å2
Refinement stepCycle: LAST / Resolution: 2.5→19.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10725 0 128 265 11118
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.01911125
X-RAY DIFFRACTIONr_bond_other_d0.0010.0210249
X-RAY DIFFRACTIONr_angle_refined_deg1.0041.9415064
X-RAY DIFFRACTIONr_angle_other_deg0.755323510
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.21351329
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.90823.937541
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.292151878
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5531558
X-RAY DIFFRACTIONr_chiral_restr0.0560.21623
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0213243
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022739
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_it0.9963.1025328
X-RAY DIFFRACTIONr_mcbond_other0.9953.1025327
X-RAY DIFFRACTIONr_mcangle_it1.7044.6496653
X-RAY DIFFRACTIONr_mcangle_other1.7044.6496654
X-RAY DIFFRACTIONr_scbond_it0.963.185797
X-RAY DIFFRACTIONr_scbond_other0.963.185798
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.6654.7358412
X-RAY DIFFRACTIONr_long_range_B_refined3.30824.54513253
X-RAY DIFFRACTIONr_long_range_B_other3.29524.56513217
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.5→2.564 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.339 118 -
Rwork0.294 2580 -
obs--77.66 %

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