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- PDB-2p4i: Evolution of a highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5... -

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Basic information

Entry
Database: PDB / ID: 2p4i
TitleEvolution of a highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor
ComponentsAngiopoietin-1 receptor
KeywordsTRANSFERASE / Tie-2 Kinase Inhibitor triazine
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 / growth factor binding / positive regulation of Rac protein signal transduction / positive regulation of focal adhesion assembly / microvillus / centriolar satellite / negative regulation of endothelial cell apoptotic process / cell surface receptor protein tyrosine kinase signaling pathway / Tie2 Signaling / response to cAMP / positive regulation of endothelial cell proliferation / transmembrane receptor protein tyrosine kinase activity / positive regulation of endothelial cell migration / substrate adhesion-dependent cell spreading / negative regulation of angiogenesis / basal plasma membrane / receptor protein-tyrosine kinase / negative regulation of inflammatory response / response to peptide hormone / 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 ERK1 and ERK2 cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / response to hypoxia / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-MR9 / Angiopoietin-1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsBellon, S.F.
CitationJournal: J.Med.Chem. / Year: 2007
Title: Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor.
Authors: Hodous, B.L. / Geuns-Meyer, S.D. / Hughes, P.E. / Albrecht, B.K. / Bellon, S. / Bready, J. / Caenepeel, S. / Cee, V.J. / Chaffee, S.C. / Coxon, A. / Emery, M. / Fretland, J. / Gallant, P. / ...Authors: Hodous, B.L. / Geuns-Meyer, S.D. / Hughes, P.E. / Albrecht, B.K. / Bellon, S. / Bready, J. / Caenepeel, S. / Cee, V.J. / Chaffee, S.C. / Coxon, A. / Emery, M. / Fretland, J. / Gallant, P. / Gu, Y. / Hoffman, D. / Johnson, R.E. / Kendall, R. / Kim, J.L. / Long, A.M. / Morrison, M. / Olivieri, P.R. / Patel, V.F. / Polverino, A. / Rose, P. / Tempest, P. / Wang, L. / Whittington, D.A. / Zhao, H.
History
DepositionMar 12, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 20, 2007Provider: repository / Type: Initial release
Revision 1.1Nov 14, 2007Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Feb 21, 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 / struct_ncs_dom_lim / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.end_auth_comp_id / _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

Downloads & links

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Assembly

Deposited unit
A: Angiopoietin-1 receptor
B: Angiopoietin-1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,6364
Polymers72,5072
Non-polymers1,1292
Water3,207178
1
A: Angiopoietin-1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,8182
Polymers36,2531
Non-polymers5651
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Angiopoietin-1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,8182
Polymers36,2531
Non-polymers5651
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)64.262, 63.189, 175.571
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22B

NCS domain segments:

Component-ID: 1 / Refine code: 4

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11VALVALTYRTYRAA838 - 90431 - 97
21GLYGLYTYRTYRBB836 - 90429 - 97
12ALAALAASPASPAA905 - 111798 - 310
22ALAALAASPASPBB905 - 111798 - 310

NCS ensembles :
ID
1
2

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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.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TEK, TIE2 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q02763, receptor protein-tyrosine kinase
#2: Chemical ChemComp-MR9 / 4-METHYL-3-({3-[2-(METHYLAMINO)PYRIMIDIN-4-YL]PYRIDIN-2-YL}OXY)-N-[2-MORPHOLIN-4-YL-5-(TRIFLUOROMETHYL)PHENYL]BENZAMIDE


Mass: 564.558 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H27F3N6O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 178 / 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: 2.46 Å3/Da / Density % sol: 49.95 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7
Details: 14-18% PEG 3350, 0.2M tri-Potassium Citrate (pH 6.5-7.5) and 2% isopropanol., pH 7.0, VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Jun 23, 2003 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.5→20 Å / Num. all: 24255 / Num. obs: 22844 / % possible obs: 94.18 % / Observed criterion σ(F): -1 / Observed criterion σ(I): -1 / Rmerge(I) obs: 0.07 / Net I/σ(I): 14.8
Reflection shellResolution: 2.5→2.59 Å / Rmerge(I) obs: 0.315 / Mean I/σ(I) obs: 2 / Num. unique all: 1897 / % possible all: 76.3

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
CrystalClear(MSC/RIGAKU)data collection
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→20 Å / Cor.coef. Fo:Fc: 0.894 / Cor.coef. Fo:Fc free: 0.842 / SU B: 10.683 / SU ML: 0.246 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.538 / ESU R Free: 0.338 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.30315 1224 5.1 %RANDOM
Rwork0.24558 ---
all0.24846 24255 --
obs0.24846 22844 94.18 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 48.907 Å2
Baniso -1Baniso -2Baniso -3
1-1.4 Å20 Å20 Å2
2--1.14 Å20 Å2
3----2.54 Å2
Refinement stepCycle: LAST / Resolution: 2.5→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3965 0 82 178 4225
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0224135
X-RAY DIFFRACTIONr_angle_refined_deg1.2221.9855613
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5495500
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.01623.778180
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.05315659
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4651525
X-RAY DIFFRACTIONr_chiral_restr0.0830.2622
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023130
X-RAY DIFFRACTIONr_nbd_refined0.2080.22009
X-RAY DIFFRACTIONr_nbtor_refined0.3050.22826
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1770.2213
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2290.262
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0950.29
X-RAY DIFFRACTIONr_mcbond_it0.5431.52613
X-RAY DIFFRACTIONr_mcangle_it0.9524024
X-RAY DIFFRACTIONr_scbond_it1.05931793
X-RAY DIFFRACTIONr_scangle_it1.6714.51589
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Refine-ID: X-RAY DIFFRACTION

Ens-IDNumberTypeRms dev position (Å)Weight position
1303medium positional0.540.5
21596medium positional0.510.5
1303medium thermal0.872
21596medium thermal0.822
LS refinement shellResolution: 2.499→2.564 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.38 71 -
Rwork0.286 1241 -
obs-1312 70.16 %

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