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- PDB-4d08: PDE2a catalytic domain in complex with a brain penetrant inhibitor -

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Basic information

Entry
Database: PDB / ID: 4d08
TitlePDE2a catalytic domain in complex with a brain penetrant inhibitor
ComponentsCGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE
KeywordsHYDROLASE / BINDING SITES / CATALYTIC DOMAIN / 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 cAMP-mediated signaling / 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 ...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 cAMP-mediated signaling / 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 / regulation of mitochondrion organization / establishment of endothelial barrier / aorta development / cGMP-mediated signaling / ventricular septum development / 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of 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 transforming growth factor beta stimulus / cellular response to cAMP / cAMP-mediated signaling / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / synaptic membrane / cellular response to mechanical stimulus / positive regulation of inflammatory response / 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 / cytosol / cytoplasm
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-Q2T / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 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 1.2May 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)167,81816
Polymers165,7304
Non-polymers2,08912
Water11,349630
1
A: CGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,9554
Polymers41,4321
Non-polymers5223
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)41,9554
Polymers41,4321
Non-polymers5223
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)41,9554
Polymers41,4321
Non-polymers5223
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)41,9554
Polymers41,4321
Non-polymers5223
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)56.040, 74.150, 92.770
Angle α, β, γ (deg.)109.04, 91.73, 91.34
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, RESDIUES 579-921
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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-Q2T / 1-(5-butoxypyridin-3-yl)-4-methyl-8-(morpholin-4-ylmethyl)[1,2,4]triazolo[4,3-a]quinoxaline


Mass: 432.518 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H28N6O2
#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.: 630 / 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: 2.33 Å3/Da / Density % sol: 47.3 % / Description: NONE
Crystal growpH: 8.2
Details: 0.2 M MAGNESIUM CHLORIDE, 0.1 M HEPES PH8.2, 20% PEG3350.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.973
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 26, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.973 Å / Relative weight: 1
ReflectionResolution: 1.9→48 Å / Num. obs: 103457 / % possible obs: 93 % / Observed criterion σ(I): 2 / Redundancy: 3.1 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 7.4
Reflection shellResolution: 1.9→2 Å / Redundancy: 3 % / Rmerge(I) obs: 0.42 / Mean I/σ(I) obs: 2.5 / % possible all: 81.7

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Processing

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

Resolution: 1.9→46.34 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.901 / SU B: 4.42 / SU ML: 0.129 / Cross valid method: THROUGHOUT / ESU R: 0.198 / ESU R Free: 0.167 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.24714 5177 5 %RANDOM
Rwork0.21289 ---
obs0.21464 98278 93.04 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.712 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å2-0.09 Å2-0.16 Å2
2---0.03 Å2-0.03 Å2
3---0.05 Å2
Refinement stepCycle: LAST / Resolution: 1.9→46.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10711 0 136 630 11477
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.01911191
X-RAY DIFFRACTIONr_bond_other_d0.0010.0210268
X-RAY DIFFRACTIONr_angle_refined_deg0.9251.94215098
X-RAY DIFFRACTIONr_angle_other_deg0.753323549
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.52551339
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.64723.876534
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.953151857
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.6771557
X-RAY DIFFRACTIONr_chiral_restr0.0530.21633
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0213091
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022718
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_it0.6842.2855359
X-RAY DIFFRACTIONr_mcbond_other0.6842.2855358
X-RAY DIFFRACTIONr_mcangle_it1.1873.4226694
X-RAY DIFFRACTIONr_mcangle_other1.1873.4226695
X-RAY DIFFRACTIONr_scbond_it0.7282.3325832
X-RAY DIFFRACTIONr_scbond_other0.7282.3335828
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.2223.4878404
X-RAY DIFFRACTIONr_long_range_B_refined2.82618.43813622
X-RAY DIFFRACTIONr_long_range_B_other2.80318.4213571
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.36 291 -
Rwork0.314 5684 -
obs--72.3 %

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