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

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Basic information

Entry
Database: PDB / ID: 6znd
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-QMZ / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.35 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 6, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 22, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 18, 2020Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / pdbx_struct_conn_angle / struct_conn
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _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
Revision 1.2Nov 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 1.3Jan 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

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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)83,8398
Polymers82,8652
Non-polymers9746
Water3,621201
1
A: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,9204
Polymers41,4321
Non-polymers4873
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,9204
Polymers41,4321
Non-polymers4873
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)171.060, 69.520, 55.090
Angle α, β, γ (deg.)90.000, 91.160, 90.000
Int Tables number5
Space group name H-MC121

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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.: 2
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.: 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-QMZ / [(3~{S})-3-([1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone


Mass: 397.428 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H23N5O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 201 / 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: 1.98 Å3/Da / Density % sol: 37.76 %
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 20 % PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Jul 24, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.35→85.51 Å / Num. obs: 26995 / % possible obs: 99.6 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.125 / Net I/σ(I): 7.3
Reflection shellResolution: 2.35→2.411 Å / Rmerge(I) obs: 0.511 / Num. unique obs: 2699

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Processing

Software
NameVersionClassification
REFMAC5.5.0072refinement
PDB_EXTRACT3.25data extraction
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1z1l

1z1l


Resolution: 2.35→85.51 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.872 / SU B: 10.445 / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.647 / ESU R Free: 0.323 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2906 1355 5 %RANDOM
Rwork0.2146 ---
obs0.2184 25640 99.54 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 69.93 Å2 / Biso mean: 25.992 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.52 Å20 Å2-1.83 Å2
2--0.69 Å20 Å2
3----1.28 Å2
Refinement stepCycle: final / Resolution: 2.35→85.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5274 0 62 201 5537
Biso mean--26.29 28.41 -
Num. residues----658
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0215467
X-RAY DIFFRACTIONr_bond_other_d0.0010.023611
X-RAY DIFFRACTIONr_angle_refined_deg1.2571.9567402
X-RAY DIFFRACTIONr_angle_other_deg0.88638781
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6865653
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.67723.87261
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.22515913
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2131527
X-RAY DIFFRACTIONr_chiral_restr0.0650.2806
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.026051
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021152
LS refinement shellResolution: 2.35→2.411 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.39 123 -
Rwork0.264 1834 -
all-1957 -
obs--96.88 %

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