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- PDB-4x3j: Selection of fragments for kinase inhibitor design: decoration is key -

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Basic information

Entry
Database: PDB / ID: 4x3j
TitleSelection of fragments for kinase inhibitor design: decoration is key
ComponentsAngiopoietin-1 receptor
KeywordsTRANSFERASE / PROTEIN KINASE / INHIBITOR COMPLEX
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 / endothelial cell proliferation / sprouting angiogenesis ...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 / endothelial cell proliferation / sprouting angiogenesis / 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 / response to cAMP / Tie2 Signaling / positive regulation of endothelial cell proliferation / transmembrane receptor protein tyrosine kinase activity / negative regulation of angiogenesis / substrate adhesion-dependent cell spreading / basal plasma membrane / positive regulation of endothelial cell migration / receptor protein-tyrosine kinase / response to peptide hormone / negative regulation of inflammatory response / response to estrogen / cell surface receptor protein tyrosine kinase signaling pathway / 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 / response to hypoxia / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of ERK1 and ERK2 cascade / receptor complex / protein kinase activity / positive regulation of protein phosphorylation / membrane raft / apical plasma membrane / phosphorylation / 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 / Fibronectin type 3 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-3WR / Angiopoietin-1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.5 Å
AuthorsCzodrowski, P. / Hoelzemann, G. / Barnickel, G. / Greiner, H. / Musil, D.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Selection of fragments for kinase inhibitor design: decoration is key.
Authors: Czodrowski, P. / Holzemann, G. / Barnickel, G. / Greiner, H. / Musil, D.
History
DepositionNov 30, 2014Deposition site: RCSB / Processing site: PDBE
Revision 1.0Dec 24, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 21, 2015Group: Database references
Revision 1.2May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: Angiopoietin-1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,2522
Polymers36,7941
Non-polymers4581
Water30617
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area11980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.456, 62.456, 178.450
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Angiopoietin-1 receptor / Endothelial tyrosine kinase / Tunica interna endothelial cell kinase / Tyrosine kinase with Ig and ...Endothelial tyrosine kinase / Tunica interna endothelial cell kinase / Tyrosine kinase with Ig and EGF homology domains-2 / Tyrosine-protein kinase receptor TEK / Tyrosine-protein kinase receptor TIE-2 / hTIE2 / p140 TEK


Mass: 36794.027 Da / Num. of mol.: 1 / Fragment: Kinase domain, UNP residues 802-1122 / Mutation: D964N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TEK, TIE2, VMCM, VMCM1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q02763, receptor protein-tyrosine kinase
#2: Chemical ChemComp-3WR / 1-[4-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea


Mass: 458.368 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H14F4N6O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 17 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.36 Å3/Da / Density % sol: 47.99 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.1 M Tris/HCl pH 7.0 0.05 M NaCl 0.03 M Lithiumsulfat

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Mar 1, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→36 Å / Num. all: 176802 / Num. obs: 12936 / % possible obs: 99.2 % / Redundancy: 13.7 % / Biso Wilson estimate: 66.7 Å2 / Net I/σ(I): 12.2

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementResolution: 2.5→35.46 Å / Cor.coef. Fo:Fc: 0.9096 / Cor.coef. Fo:Fc free: 0.9053 / SU R Cruickshank DPI: 0.39 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.405 / SU Rfree Blow DPI: 0.285 / SU Rfree Cruickshank DPI: 0.284
RfactorNum. reflection% reflectionSelection details
Rfree0.2933 629 4.88 %RANDOM
Rwork0.2546 ---
obs0.2565 12878 99.61 %-
Displacement parametersBiso mean: 75.92 Å2
Baniso -1Baniso -2Baniso -3
1--6.2222 Å20 Å20 Å2
2---6.2222 Å20 Å2
3---12.4444 Å2
Refine analyzeLuzzati coordinate error obs: 0.49 Å
Refinement stepCycle: 1 / Resolution: 2.5→35.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1887 0 33 17 1937
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011962HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.122662HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d668SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes47HARMONIC2
X-RAY DIFFRACTIONt_gen_planes281HARMONIC5
X-RAY DIFFRACTIONt_it1962HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.81
X-RAY DIFFRACTIONt_other_torsion20.8
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion246SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2293SEMIHARMONIC4
LS refinement shellResolution: 2.5→2.74 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.313 147 4.96 %
Rwork0.2572 2814 -
all0.26 2961 -
obs--99.61 %
Refinement TLS params.Method: refined / Origin x: 25.7044 Å / Origin y: 16.0967 Å / Origin z: 56.5154 Å
111213212223313233
T-0.2647 Å20.0012 Å20.009 Å2-0.0918 Å20.0823 Å2---0.3026 Å2
L1.5547 °2-0.1783 °2-0.7486 °2-1.5491 °2-0.3666 °2--4.5186 °2
S-0.1157 Å °0.0315 Å °0.056 Å °-0.1288 Å °0.2445 Å °-0.0201 Å °0.0944 Å °-0.3135 Å °-0.1288 Å °
Refinement TLS groupSelection details: { A|* }

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