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

+
Open data


ID or keywords:

Loading...

-
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


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
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 ...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
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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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

-
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

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
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

-
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

-
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 %

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbjlvh1.pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more