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- PDB-3l8p: Crystal structure of cytoplasmic kinase domain of Tie2 complexed ... -

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Basic information

Entry
Database: PDB / ID: 3l8p
TitleCrystal structure of cytoplasmic kinase domain of Tie2 complexed with inhibitor CEP11207
ComponentsAngiopoietin-1 receptor
KeywordsTRANSFERASE / receptor tyrosine kinase / cytoplasmic kinase domain / Tie2 / inhibitor CEP11207 / ATP-binding / Disease mutation / Glycoprotein / Kinase / Membrane / Nucleotide-binding / Phosphoprotein / Receptor / Tyrosine-protein kinase
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 / endochondral ossification / regulation of vascular permeability / 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 / endochondral ossification / regulation of vascular permeability / heart trabecula formation / definitive hemopoiesis / endothelial cell proliferation / sprouting angiogenesis / positive regulation of Rho protein signal transduction / growth factor binding / positive regulation of Rac protein signal transduction / positive regulation of intracellular signal transduction / microvillus / positive regulation of focal adhesion assembly / negative regulation of endothelial cell apoptotic process / response to cAMP / Tie2 Signaling / positive regulation of endothelial cell proliferation / transmembrane receptor protein tyrosine kinase activity / positive regulation of endothelial cell migration / substrate adhesion-dependent cell spreading / cell surface receptor protein tyrosine kinase signaling pathway / negative regulation of angiogenesis / basal plasma membrane / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / negative regulation of inflammatory response / response to estrogen / cellular response to mechanical stimulus / positive regulation of angiogenesis / cell-cell junction / cell-cell signaling / signaling receptor activity / heart development / RAF/MAP kinase cascade / basolateral plasma membrane / angiogenesis / response to hypoxia / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / protein kinase activity / positive regulation of MAPK cascade / ciliary basal body / apical plasma membrane / membrane raft / focal adhesion / centrosome / 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. / Fibronectin type III domain / EGF-like domain signature 1. / : / EGF-like domain signature 2. / 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. / Fibronectin type III domain / EGF-like domain signature 1. / : / EGF-like domain signature 2. / 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 / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Immunoglobulin-like domain superfamily / Transferase(Phosphotransferase); domain 1 / 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-0CE / Angiopoietin-1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsFedorov, A.A. / Fedorov, E.V. / Pauletti, D. / Meyer, S.L. / Hudkins, R.L. / Almo, S.C.
CitationJournal: To be Published
Title: Crystal structure of cytoplasmic kinase domain of Tie2 complexed with inhibitor CEP11207
Authors: Fedorov, A.A. / Fedorov, E.V. / Pauletti, D. / Meyer, S.L. / Hudkins, R.L. / Almo, S.C.
History
DepositionJan 3, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 6, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: 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 / pdbx_initial_refinement_model / 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

Downloads & links

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Assembly

Deposited unit
A: Angiopoietin-1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7062
Polymers36,2531
Non-polymers4531
Water70339
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.602, 85.602, 107.344
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number94
Space group name H-MP42212

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Components

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


Mass: 36253.328 Da / Num. of mol.: 1 / Fragment: Tie2 fragment 808-1124
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-0CE / 2-methyl-11-(1-methylethyl)-8-[(2S)-tetrahydro-2H-pyran-2-yl]-2,11,12,13-tetrahydro-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one


Mass: 452.548 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H28N4O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 39 / 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: 2.71 Å3/Da / Density % sol: 54.65 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 8% PEG 3350, 0.2M Tri-Ammonium Citrate, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 277.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X4A / Wavelength: 0.97915 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jun 21, 2003
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 2.4→25 Å / Num. all: 16055 / Num. obs: 16055 / % possible obs: 99.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.7 % / Biso Wilson estimate: 27.4 Å2 / Rmerge(I) obs: 0.061

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
EPMRphasing
CNS1.1refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1FVR

1fvr


Resolution: 2.4→24.17 Å / Rfactor Rfree error: 0.009 / Data cutoff high absF: 4165530.36 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.265 827 5.2 %RANDOM
Rwork0.238 ---
all0.239 16055 --
obs0.238 16055 99.2 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 29.6277 Å2 / ksol: 0.334281 e/Å3
Displacement parametersBiso mean: 42.8 Å2
Baniso -1Baniso -2Baniso -3
1--6.39 Å20 Å20 Å2
2---6.39 Å20 Å2
3---12.78 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.38 Å0.33 Å
Luzzati d res low-5 Å
Luzzati sigma a0.35 Å0.22 Å
Refinement stepCycle: LAST / Resolution: 2.4→24.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2348 0 34 39 2421
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_dihedral_angle_d21.9
X-RAY DIFFRACTIONc_improper_angle_d0.76
X-RAY DIFFRACTIONc_mcbond_it1.51.5
X-RAY DIFFRACTIONc_mcangle_it2.572
X-RAY DIFFRACTIONc_scbond_it1.922
X-RAY DIFFRACTIONc_scangle_it2.932.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.4→2.49 Å / Rfactor Rfree error: 0.045 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.386 72 4.6 %
Rwork0.291 1508 -
obs-1508 99.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3ion.paramion.top
X-RAY DIFFRACTION4INH_par.txt&_1_TOPOLOGY_INFILE_4
X-RAY DIFFRACTION5&_1_PARAMETER_INFILE_5&_1_TOPOLOGY_INFILE_5

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