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- PDB-4jib: Crystal structure of of PDE2-inhibitor complex -

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Basic information

Entry
Database: PDB / ID: 4jib
TitleCrystal structure of of PDE2-inhibitor complex
ComponentscGMP-dependent 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / 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 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-1L6 / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.72 Å
AuthorsPandit, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery of potent, selective, bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model, Part I: Transformation of selective pyrazolodiazepinone ...Title: Discovery of potent, selective, bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model, Part I: Transformation of selective pyrazolodiazepinone phosphodiesterase 4 (PDE4) inhibitors into selective PDE2 inhibitors.
Authors: Plummer, M.S. / Cornicelli, J. / Roark, H. / Skalitzky, D.J. / Stankovic, C.J. / Bove, S. / Pandit, J. / Goodman, A. / Hicks, J. / Shahripour, A. / Beidler, D. / Lu, X.K. / Sanchez, B. / ...Authors: Plummer, M.S. / Cornicelli, J. / Roark, H. / Skalitzky, D.J. / Stankovic, C.J. / Bove, S. / Pandit, J. / Goodman, A. / Hicks, J. / Shahripour, A. / Beidler, D. / Lu, X.K. / Sanchez, B. / Whitehead, C. / Sarver, R. / Braden, T. / Gowan, R. / Shen, X.Q. / Welch, K. / Ogden, A. / Sadagopan, N. / Baum, H. / Miller, H. / Banotai, C. / Spessard, C. / Lightle, S.
History
DepositionMar 5, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2013Provider: repository / Type: Initial release
Revision 1.1May 22, 2013Group: Database references
Revision 1.2Nov 15, 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: 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)162,94116
Polymers160,9004
Non-polymers2,04112
Water25,8521435
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10450 Å2
ΔGint-229 kcal/mol
Surface area57280 Å2
Unit cell
Length a, b, c (Å)55.880, 74.132, 91.802
Angle α, β, γ (deg.)109.670, 88.720, 88.970
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


Mass: 40225.102 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE2A / 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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Chemical
ChemComp-1L6 / 1-(2-hydroxyethyl)-3-(2-methylbutan-2-yl)-5-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8(1H)-one


Mass: 420.507 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H28N6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1435 / 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: 2.22 Å3/Da / Density % sol: 44.7 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.72→86.39 Å / Num. obs: 142966 / % possible obs: 96.2 % / Redundancy: 3.9 % / Rmerge(I) obs: 0.066 / Χ2: 1.391 / Net I/σ(I): 11.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.72-1.783.60.452127730.825185.9
1.78-1.853.90.363142570.876196.1
1.85-1.9440.273143701.106196.4
1.94-2.0440.176143211.005196.7
2.04-2.1740.126144051.268197
2.17-2.3340.1145021.516197.4
2.33-2.5740.074145311.615197.8
2.57-2.943.90.062146111.761198.2
2.94-3.713.90.049146582.147198.7
3.71-503.80.043145381.668197.9

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.11data extraction
DENZOdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.72→50 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.929 / WRfactor Rfree: 0.2346 / WRfactor Rwork: 0.1849 / Occupancy max: 1 / Occupancy min: 0.33 / FOM work R set: 0.8298 / SU B: 2.608 / SU ML: 0.087 / SU R Cruickshank DPI: 0.128 / SU Rfree: 0.1296 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.128 / ESU R Free: 0.13 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2402 7141 5 %RANDOM
Rwork0.188 ---
obs0.1905 142327 96.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 59.03 Å2 / Biso mean: 23.7846 Å2 / Biso min: 4.76 Å2
Baniso -1Baniso -2Baniso -3
1--1.04 Å20.54 Å20.9 Å2
2--0.59 Å20.01 Å2
3---0.39 Å2
Refinement stepCycle: LAST / Resolution: 1.72→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10935 0 132 1435 12502
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.02111401
X-RAY DIFFRACTIONr_angle_refined_deg1.491.96215393
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.02651334
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.40323.887566
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.992152056
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0851566
X-RAY DIFFRACTIONr_chiral_restr0.0930.21639
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.028648
X-RAY DIFFRACTIONr_nbd_refined0.2090.25915
X-RAY DIFFRACTIONr_nbtor_refined0.3080.27923
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1250.21028
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1730.2131
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1330.254
X-RAY DIFFRACTIONr_mcbond_it0.9421.56883
X-RAY DIFFRACTIONr_mcangle_it1.458210820
X-RAY DIFFRACTIONr_scbond_it2.49635107
X-RAY DIFFRACTIONr_scangle_it3.6144.54573
LS refinement shellResolution: 1.72→1.765 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.343 469 -
Rwork0.265 9231 -
all-9700 -
obs--88.45 %

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