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- PDB-5u7k: PDE2 catalytic domain complexed with inhibitors -

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Basic information

Entry
Database: PDB / ID: 5u7k
TitlePDE2 catalytic domain complexed with inhibitors
ComponentscGMP-dependent 3',5'-cyclic phosphodiesterase
KeywordsHydrolase/Hydrolase Inhibitor / PDE2 / SBDD / inhibitor / phosphodiesterase / Hydrolase-Hydrolase Inhibitor complex
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 / TPR domain binding / cGMP-mediated signaling / 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-7Y1 / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.06 Å
AuthorsPandit, J. / Parris, K.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor.
Authors: Helal, C.J. / Arnold, E.P. / Boyden, T.L. / Chang, C. / Chappie, T.A. / Fennell, K.F. / Forman, M.D. / Hajos, M. / Harms, J.F. / Hoffman, W.E. / Humphrey, J.M. / Kang, Z. / Kleiman, R.J. / ...Authors: Helal, C.J. / Arnold, E.P. / Boyden, T.L. / Chang, C. / Chappie, T.A. / Fennell, K.F. / Forman, M.D. / Hajos, M. / Harms, J.F. / Hoffman, W.E. / Humphrey, J.M. / Kang, Z. / Kleiman, R.J. / Kormos, B.L. / Lee, C.W. / Lu, J. / Maklad, N. / McDowell, L. / Mente, S. / O'Connor, R.E. / Pandit, J. / Piotrowski, M. / Schmidt, A.W. / Schmidt, C.J. / Ueno, H. / Verhoest, P.R. / Yang, E.X.
History
DepositionDec 12, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 28, 2017Provider: repository / Type: Initial release
Revision 1.1Jul 26, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2Oct 4, 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

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)162,74417
Polymers160,9004
Non-polymers1,84413
Water11,385632
1
A: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6774
Polymers40,2251
Non-polymers4523
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)40,6774
Polymers40,2251
Non-polymers4523
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)40,7135
Polymers40,2251
Non-polymers4884
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)40,6774
Polymers40,2251
Non-polymers4523
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)55.866, 73.508, 91.494
Angle α, β, γ (deg.)109.380, 91.230, 90.670
Int Tables number1
Space group name H-MP1

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
cGMP-dependent 3',5'-cyclic phosphodiesterase / Cyclic GMP-stimulated phosphodiesterase / cGSPDE


Mass: 40225.102 Da / Num. of mol.: 4 / Fragment: Catalytic domain of PDE2, UNP residues 323-663
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE2A / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf21
References: UniProt: O00408, 3',5'-cyclic-nucleotide phosphodiesterase

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Non-polymers , 5 types, 645 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Chemical
ChemComp-7Y1 / 3-[5-(4-ethylphenyl)-1-methyl-1H-pyrazol-4-yl]-5-propoxy[1,2,4]triazolo[4,3-a]pyrazine


Mass: 362.428 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H22N6O
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 632 / 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: 2.2 Å3/Da / Density % sol: 44.14 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / Details: 25% PEG 3350, 0.1 M Tris, pH 8.5, and 0.2 M MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Aug 13, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.05→100 Å / Num. obs: 81915 / % possible obs: 96.8 % / Redundancy: 1.9 % / Rmerge(I) obs: 0.049 / Χ2: 0.982 / Net I/σ(I): 9.1 / Num. measured all: 158012
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.05-2.121.80.29877061.111191
2.12-2.211.90.27880900.926195.7
2.21-2.311.90.23480451.224195.3
2.31-2.4320.19282650.938197.4
2.43-2.5820.1482230.966197.6
2.58-2.7820.10183350.936197.8
2.78-3.0620.06682680.865198.2
3.06-3.5120.03783370.856198.4
3.51-4.4220.02583190.918198.4
4.42-1001.90.02383271.129198.3

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
REFMAC5.2.0019refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
HKL-2000data reduction
HKL-2000data reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ITU

3itu


Resolution: 2.06→36 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.925 / WRfactor Rfree: 0.2393 / WRfactor Rwork: 0.1753 / FOM work R set: 0.7327 / SU B: 7.86 / SU ML: 0.196 / SU R Cruickshank DPI: 0.2548 / SU Rfree: 0.2109 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.255 / ESU R Free: 0.211 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2547 4077 5 %RANDOM
Rwork0.1922 ---
obs0.1953 77824 96.19 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 116.37 Å2 / Biso mean: 36.75 Å2 / Biso min: 7.62 Å2
Baniso -1Baniso -2Baniso -3
1--1.16 Å2-0.22 Å2-1.57 Å2
2--0.95 Å2-0.28 Å2
3----0.04 Å2
Refinement stepCycle: final / Resolution: 2.06→36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11035 0 117 632 11784
Biso mean--28 34.82 -
Num. residues----1349
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.02111521
X-RAY DIFFRACTIONr_angle_refined_deg1.5141.95915573
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.53551377
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.44223.835571
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.705152072
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.5211568
X-RAY DIFFRACTIONr_chiral_restr0.1160.21661
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.028754
X-RAY DIFFRACTIONr_nbd_refined0.2390.25722
X-RAY DIFFRACTIONr_nbtor_refined0.3220.27927
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.20.2690
X-RAY DIFFRACTIONr_metal_ion_refined0.0730.26
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2350.2113
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2690.235
LS refinement shellResolution: 2.058→2.111 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.395 245 -
Rwork0.325 4880 -
all-5125 -
obs--81.69 %

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