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- PDB-2wqb: Structure of the Tie2 kinase domain in complex with a thiazolopyr... -

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Basic information

Entry
Database: PDB / ID: 2wqb
TitleStructure of the Tie2 kinase domain in complex with a thiazolopyrimidine inhibitor
ComponentsANGIOPOIETIN-1 RECEPTOR
KeywordsTRANSFERASE / PHOSPHOPROTEIN / KINASE / RECEPTOR / ONCOLOGY / ATP-BINDING / GLYCOPROTEIN / TYROSINE-PROTEIN KINASE / PHOSPHOTRANSFERASE / NUCLEOTIDE-BINDING / DISEASE MUTATION / THIAZOLOPYRIMIDINE
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-QQ1 / Angiopoietin-1 receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.95 Å
AuthorsBrassington, C. / Breed, J. / Buttar, D. / Fitzek, M. / Forder, C. / Hassall, L. / Hayter, B.R. / Jones, C.D. / Luke, R.W.A. / McCall, E. ...Brassington, C. / Breed, J. / Buttar, D. / Fitzek, M. / Forder, C. / Hassall, L. / Hayter, B.R. / Jones, C.D. / Luke, R.W.A. / McCall, E. / McCoull, W. / Norman, R. / Paterson, D. / McMiken, H. / Rowsell, S. / Tucker, J.A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Novel Thienopyrimidine and Thiazolopyrimidine Kinase Inhibitors with Activity Against Tie-2 in Vitro and in Vivo.
Authors: Luke, R.W. / Ballard, P. / Buttar, D. / Campbell, L. / Curwen, J. / Emery, S.C. / Griffen, A.M. / Hassall, L. / Hayter, B.R. / Jones, C.D. / Mccoull, W. / Mellor, M. / Swain, M.L. / Tucker, J.A.
History
DepositionAug 18, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 3, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Apr 17, 2013Group: Derived calculations / Refinement description
Revision 1.3Mar 6, 2019Group: Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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 / _pdbx_database_status.status_code_sf / _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)37,3842
Polymers36,9931
Non-polymers3911
Water34219
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)80.164, 108.791, 101.573
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-2010-

HOH

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Components

#1: Protein ANGIOPOIETIN-1 RECEPTOR / TYROSINE-PROTEIN KINASE RECEPTOR TIE-2 / TIE2 KINASE / TYROSINE-PROTEIN KINASE RECEPTOR TEK / ...TYROSINE-PROTEIN KINASE RECEPTOR TIE-2 / TIE2 KINASE / TYROSINE-PROTEIN KINASE RECEPTOR TEK / TUNICA INTERNA ENDOTHELIAL CELL KINASE / P140 TEK / HTIE2


Mass: 36993.234 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 802-1124 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9
References: UniProt: Q02763, receptor protein-tyrosine kinase
#2: Chemical ChemComp-QQ1 / 2-[3-(CYCLOHEXYLMETHYL)-5-PHENYL-IMIDAZOL-4-YL]-[1,3]THIAZOLO[4,5-E]PYRIMIDIN-7-AMINE


Mass: 390.505 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H22N6S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 19 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, ASP 964 TO ASN
Sequence detailsMUTATION AT D964N TO RENDER EXPRESSED PROTEIN KINASE DEAD. ADDITIONAL G AT N-TERMINUS FROM CLONING.

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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: 3.36 Å3/Da / Density % sol: 63 % / Description: NONE
Crystal growTemperature: 293 K / pH: 7.5
Details: 5 MG/ML PROTEIN, 5% (W/V) PEG6000, 5% (V/V) MPD, 100MM MOPS PH7.5, 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SRS / Beamline: PX14.2 / Wavelength: 0.975
DetectorType: ADSC CCD / Detector: CCD / Date: Jun 19, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.975 Å / Relative weight: 1
ReflectionResolution: 2.95→32.97 Å / Num. obs: 9451 / % possible obs: 98.3 % / Observed criterion σ(I): 3.7 / Redundancy: 5.3 % / Biso Wilson estimate: 45 Å2 / Rmerge(I) obs: 0.12 / Net I/σ(I): 12.2
Reflection shellResolution: 2.95→3.11 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.44 / Mean I/σ(I) obs: 1.78 / % possible all: 99.1

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Processing

Software
NameVersionClassification
REFMAC5.5.0088refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1FVR

1fvr


Resolution: 2.95→32.97 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.91 / SU B: 32.445 / SU ML: 0.293 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R Free: 0.404 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. ATOM RECORD CONTAINS RESIDUAL B FACTORS ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.25858 445 4.8 %RANDOM
Rwork0.19568 ---
obs0.19873 8822 95.97 %-
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: 35.362 Å2
Baniso -1Baniso -2Baniso -3
1--3.75 Å20 Å20 Å2
2---2.84 Å20 Å2
3---6.59 Å2
Refinement stepCycle: LAST / Resolution: 2.95→32.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2286 0 28 19 2333
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0222367
X-RAY DIFFRACTIONr_bond_other_d0.0010.021599
X-RAY DIFFRACTIONr_angle_refined_deg1.4941.9543207
X-RAY DIFFRACTIONr_angle_other_deg0.92633871
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4015285
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.0823.426108
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.8215392
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7051517
X-RAY DIFFRACTIONr_chiral_restr0.0780.2347
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022657
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02506
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.7711.51432
X-RAY DIFFRACTIONr_mcbond_other0.0961.5586
X-RAY DIFFRACTIONr_mcangle_it1.45622285
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.7263935
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.964.5922
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.95→3.026 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.382 19 -
Rwork0.217 638 -
obs--94.26 %
Refinement TLS params.Method: refined / Origin x: 39.2386 Å / Origin y: 35.5125 Å / Origin z: 48.9909 Å
111213212223313233
T0.0632 Å20.0206 Å20.0191 Å2-0.0729 Å2-0.0107 Å2--0.0383 Å2
L0.6862 °20.0482 °2-0.1069 °2-1.5581 °2-0.2535 °2--0.7759 °2
S-0.0202 Å °0.0699 Å °-0.098 Å °-0.0508 Å °0.0157 Å °0.0274 Å °0.011 Å °-0.1188 Å °0.0045 Å °

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