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- PDB-6cyc: PDE2 in complex with compound 5 -

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Basic information

Entry
Database: PDB / ID: 6cyc
TitlePDE2 in complex with compound 5
ComponentscGMP-dependent 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PDE2 / inhibition / structure-guided design / 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 / ventricular septum development / 3',5'-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 / cAMP-mediated signaling / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / 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 / 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-FKJ / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.54 Å
AuthorsLu, J.
CitationJournal: ACS Med Chem Lett / Year: 2018
Title: Structure-Guided Design and Procognitive Assessment of a Potent and Selective Phosphodiesterase 2A Inhibitor.
Authors: Stachel, S.J. / Berger, R. / Nomland, A.B. / Ginnetti, A.T. / Paone, D.V. / Wang, D. / Puri, V. / Lange, H. / Drott, J. / Lu, J. / Marcus, J. / Dwyer, M.P. / Suon, S. / Uslaner, J.M. / Smith, S.M.
History
DepositionApr 5, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 19, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: 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_struct_conn_angle / software / 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 / _software.name / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,96019
Polymers87,3902
Non-polymers1,57117
Water7,206400
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4600 Å2
ΔGint-59 kcal/mol
Surface area28000 Å2
Unit cell
Length a, b, c (Å)72.250, 96.410, 101.650
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 cGMP-dependent 3',5'-cyclic phosphodiesterase / Cyclic GMP-stimulated phosphodiesterase / cGSPDE


Mass: 43694.797 Da / Num. of mol.: 2
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

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Non-polymers , 5 types, 417 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-FKJ / 3-(hydroxymethyl)-1-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione


Mass: 354.284 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H13F3N4O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 400 / 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: 2.03 Å3/Da / Density % sol: 39.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 12% PEG8000, 0.1M Hepes pH7.5, 1mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Aug 2, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.54→38.17 Å / Num. obs: 105238 / % possible obs: 99.9 % / Redundancy: 6.5 % / Biso Wilson estimate: 20.78 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 13.4
Reflection shellResolution: 1.54→1.62 Å / Redundancy: 6.5 % / Rmerge(I) obs: 0.68 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
autoPROCdata scaling
REFMACphasing
RefinementResolution: 1.54→38.17 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.947 / SU R Cruickshank DPI: 0.078 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.08 / SU Rfree Blow DPI: 0.077 / SU Rfree Cruickshank DPI: 0.076
RfactorNum. reflection% reflectionSelection details
Rfree0.205 5255 5 %RANDOM
Rwork0.185 ---
obs0.186 105149 99.8 %-
Displacement parametersBiso mean: 24.15 Å2
Baniso -1Baniso -2Baniso -3
1-4.6023 Å20 Å20 Å2
2---1.2742 Å20 Å2
3----3.328 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: 1 / Resolution: 1.54→38.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5540 0 98 400 6038
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015838HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.967893HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2022SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes135HARMONIC8
X-RAY DIFFRACTIONt_gen_planes898HARMONIC8
X-RAY DIFFRACTIONt_it5838HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.58
X-RAY DIFFRACTIONt_other_torsion16.25
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion751SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7454SEMIHARMONIC4
LS refinement shellResolution: 1.54→1.58 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.22 415 5.56 %
Rwork0.1985 7053 -
all0.1997 7468 -
obs--97.52 %

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