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- PDB-6zqz: [1,2,4]Triazolo[1,5-a]pyrimidine Phosphodiesterase 2 Inhibitors -

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Basic information

Entry
Database: PDB / ID: 6zqz
Title[1,2,4]Triazolo[1,5-a]pyrimidine Phosphodiesterase 2 Inhibitors
ComponentscGMP-dependent 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE / PDE2A inhibitor / FEP / SBDD / Free energy perturbation / molecular dynamics / Alzheimers disease / phosphodiesterase / molecular design / binding free energy
Function / homology
Function and homology information


: / 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 / heart valve development / positive regulation of vascular permeability / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of vascular permeability / establishment of endothelial barrier ...: / 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 / heart valve development / positive regulation of vascular permeability / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of vascular permeability / establishment of endothelial barrier / regulation of mitochondrion organization / : / 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / aorta development / ventricular septum development / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cGMP effects / phosphate ion binding / TPR domain binding / cGMP binding / monocyte differentiation / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cellular response to transforming growth factor beta stimulus / : / cAMP binding / synaptic membrane / cellular response to cAMP / cellular response to mechanical stimulus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cellular response to xenobiotic stimulus / positive regulation of inflammatory response / presynaptic membrane / G alpha (s) signalling events / mitochondrial outer membrane / mitochondrial inner membrane / mitochondrial matrix / positive regulation of gene expression / perinuclear region of cytoplasm / magnesium ion binding / endoplasmic reticulum / negative regulation of transcription by RNA polymerase II / Golgi apparatus / protein homodimerization activity / zinc ion binding / identical protein binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
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 ...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 / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / GAF-like domain superfamily
Similarity search - Domain/homology
Chem-QOQ / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.88 Å
AuthorsTresadern, G. / Leonard, P.M.
CitationJournal: J.Med.Chem. / Year: 2020
Title: [1,2,4]Triazolo[1,5- a ]pyrimidine Phosphodiesterase 2A Inhibitors: Structure and Free-Energy Perturbation-Guided Exploration.
Authors: Tresadern, G. / Velter, I. / Trabanco, A.A. / Van den Keybus, F. / Macdonald, G.J. / Somers, M.V.F. / Vanhoof, G. / Leonard, P.M. / Lamers, M.B.A.C. / Van Roosbroeck, Y.E.M. / Buijnsters, P.J.J.A.
History
DepositionJul 10, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 4, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 25, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)167,68417
Polymers165,7304
Non-polymers1,95413
Water16,394910
1
A: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules

C: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,8308
Polymers82,8652
Non-polymers9656
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_666x+1,y+1,z+11
Buried area3120 Å2
ΔGint-115 kcal/mol
Surface area28120 Å2
MethodPISA
2
B: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules

D: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,8549
Polymers82,8652
Non-polymers9897
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_454x-1,y,z-11
Buried area2940 Å2
ΔGint-116 kcal/mol
Surface area28450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.960, 73.460, 92.230
Angle α, β, γ (deg.)109.160, 91.370, 91.260
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 / cGSPDE


Mass: 41432.375 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE2A / Cell line (production host): Sf9 / 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.: 5 / Source method: obtained synthetically / Formula: Mg
#4: Chemical
ChemComp-QOQ / 5-[bis(fluoranyl)methyl]-7-[(3~{S})-1-[(2-chloranyl-6-methyl-pyridin-4-yl)methyl]piperidin-3-yl]-[1,2,4]triazolo[1,5-a]pyrimidine


Mass: 392.833 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H19ClF2N6 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 910 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.16 Å3/Da / Density % sol: 43.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 0.2 M MgCl2, 0.1 M Tris-HCl pH 8.0 and 24 % PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 11, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.88→87.07 Å / Num. obs: 105695 / % possible obs: 93.4 % / Redundancy: 1.7 % / Rmerge(I) obs: 0.067 / Net I/σ(I): 7
Reflection shellResolution: 1.88→1.93 Å / Rmerge(I) obs: 0.261 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 10569

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
PDB_EXTRACT3.25data extraction
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1z1l

1z1l


Resolution: 1.88→87.07 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.911 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.181 / ESU R Free: 0.164 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2441 5262 5 %RANDOM
Rwork0.1964 ---
obs0.1988 100432 93.43 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 57.3 Å2 / Biso mean: 18.672 Å2 / Biso min: 7.5 Å2
Baniso -1Baniso -2Baniso -3
1--0.88 Å2-0.04 Å2-0.86 Å2
2--0.53 Å20.11 Å2
3---0.39 Å2
Refinement stepCycle: final / Resolution: 1.88→87.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10767 0 117 910 11794
Biso mean--20.19 26.32 -
Num. residues----1339
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0211172
X-RAY DIFFRACTIONr_bond_other_d00.027427
X-RAY DIFFRACTIONr_angle_refined_deg1.1561.95615137
X-RAY DIFFRACTIONr_angle_other_deg4.141318060
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.01751341
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.69723.796540
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.566151885
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0811560
X-RAY DIFFRACTIONr_chiral_restr0.0640.21650
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212382
X-RAY DIFFRACTIONr_gen_planes_other0.0060.022374
LS refinement shellResolution: 1.88→1.927 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.317 390 -
Rwork0.281 7170 -
obs--90.42 %

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