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- PDB-2osc: Synthesis, Structural Analysis, and SAR Studies of Triazine Deriv... -

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Basic information

Entry
Database: PDB / ID: 2osc
TitleSynthesis, Structural Analysis, and SAR Studies of Triazine Derivatives as Potent, Selective Tie-2 Inhibitors
ComponentsAngiopoietin-1 receptor
KeywordsTRANSFERASE / Kinase domain Tie-2
Function / homology
Function and homology information


Tie signaling pathway / glomerulus vasculature development / regulation of establishment or maintenance of cell polarity / regulation of endothelial cell apoptotic process / regulation of vascular permeability / endochondral ossification / heart trabecula formation / definitive hemopoiesis / sprouting angiogenesis / endothelial cell proliferation ...Tie signaling pathway / glomerulus vasculature development / regulation of establishment or maintenance of cell polarity / regulation of endothelial cell apoptotic process / regulation of vascular permeability / endochondral ossification / heart trabecula formation / definitive hemopoiesis / sprouting angiogenesis / endothelial cell proliferation / positive regulation of intracellular signal transduction / positive regulation of Rho protein signal transduction / positive regulation of Rac protein signal transduction / growth factor binding / positive regulation of focal adhesion assembly / microvillus / centriolar satellite / negative regulation of endothelial cell apoptotic process / Tie2 Signaling / response to cAMP / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of endothelial cell proliferation / positive regulation of endothelial cell migration / transmembrane receptor protein tyrosine kinase activity / negative regulation of angiogenesis / substrate adhesion-dependent cell spreading / basal plasma membrane / receptor protein-tyrosine kinase / response to peptide hormone / negative regulation of inflammatory response / response to estrogen / positive regulation of angiogenesis / cell-cell junction / cell-cell signaling / signaling receptor activity / heart development / RAF/MAP kinase cascade / basolateral plasma membrane / angiogenesis / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of ERK1 and ERK2 cascade / response to hypoxia / receptor complex / protein kinase activity / positive regulation of protein phosphorylation / membrane raft / apical plasma membrane / focal adhesion / negative regulation of apoptotic process / cell surface / extracellular region / ATP binding / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
Tyrosine-protein kinase, receptor Tie-2, Ig-like domain 1, N-terminal / Tie-2 Ig-like domain 1 / Laminin-type EGF domain / : / Epidermal growth factor-like domain. / EGF-like domain profile. / EGF-like domain signature 2. / EGF-like domain signature 1. / Fibronectin type III domain / EGF-like domain ...Tyrosine-protein kinase, receptor Tie-2, Ig-like domain 1, N-terminal / Tie-2 Ig-like domain 1 / Laminin-type EGF domain / : / Epidermal growth factor-like domain. / EGF-like domain profile. / EGF-like domain signature 2. / EGF-like domain signature 1. / Fibronectin type III domain / EGF-like domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-MUH / Angiopoietin-1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsBellon, S.F. / Kim, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: Synthesis, structural analysis, and SAR studies of triazine derivatives as potent, selective Tie-2 inhibitors.
Authors: Hodous, B.L. / Geuns-Meyer, S.D. / Hughes, P.E. / Albrecht, B.K. / Bellon, S. / Caenepeel, S. / Cee, V.J. / Chaffee, S.C. / Emery, M. / Fretland, J. / Gallant, P. / Gu, Y. / Johnson, R.E. / ...Authors: Hodous, B.L. / Geuns-Meyer, S.D. / Hughes, P.E. / Albrecht, B.K. / Bellon, S. / Caenepeel, S. / Cee, V.J. / Chaffee, S.C. / Emery, M. / Fretland, J. / Gallant, P. / Gu, Y. / Johnson, R.E. / Kim, J.L. / Long, A.M. / Morrison, M. / Olivieri, P.R. / Patel, V.F. / Polverino, A. / Rose, P. / Wang, L. / Zhao, H.
History
DepositionFeb 5, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 20, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.4Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

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Assembly

Deposited unit
A: Angiopoietin-1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7032
Polymers36,2531
Non-polymers4491
Water84747
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)62.995, 62.995, 178.814
Angle α, β, γ (deg.)90, 90, 90
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Angiopoietin-1 receptor / Tyrosine-protein kinase receptor TIE-2 / hTIE2 / Tyrosine-protein kinase receptor TEK / p140 TEK / ...Tyrosine-protein kinase receptor TIE-2 / hTIE2 / Tyrosine-protein kinase receptor TEK / p140 TEK / Tunica interna endothelial cell kinase / CD202b antigen


Mass: 36253.328 Da / Num. of mol.: 1 / Fragment: Tie-2 Kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TEK, TIE2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q02763, receptor protein-tyrosine kinase
#2: Chemical ChemComp-MUH / N-{4-METHYL-3-[(3-PYRIMIDIN-4-YLPYRIDIN-2-YL)AMINO]PHENYL}-3-(TRIFLUOROMETHYL)BENZAMIDE


Mass: 449.428 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H18F3N5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 47 / 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: 2.45 Å3/Da / Density % sol: 49.71 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 14-18 % (w/v) PEG 3350, and 0.2 M tri-Potassium Citrate (pH 6.5-7.5), and 2% (v/v) isopropanol, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Jul 1, 2003 / Details: osmic
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. all: 9506 / Num. obs: 8780 / % possible obs: 92.4 % / Observed criterion σ(F): -1 / Observed criterion σ(I): -1
Reflection shellResolution: 2.8→2.93 Å

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Processing

Software
NameVersionClassification
CrystalClear(MSC/RIGAKU)data collection
AMoREphasing
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→50 Å / σ(F): 0
RfactorNum. reflection% reflection
Rfree0.3057 433 -
Rwork0.2506 --
all-9506 -
obs-8780 92.4 %
Refinement stepCycle: LAST / Resolution: 2.8→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1991 0 33 47 2071
LS refinement shellResolution: 2.8→2.93 Å
RfactorNum. reflection
Rfree0.3363 49
Rwork0.2705 -
obs-1028

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