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- PDB-2oh4: Crystal structure of Vegfr2 with a benzimidazole-urea inhibitor -

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Basic information

Entry
Database: PDB / ID: 2oh4
TitleCrystal structure of Vegfr2 with a benzimidazole-urea inhibitor
ComponentsVascular endothelial growth factor receptor 2VEGF receptor
KeywordsTRANSFERASE / Vascular endothelial growth factor receptor 2 / Tyrosine-protein kinase / Angiogenesis / ATP-binding / Phosphorylation / Kinase insert domain receptor / Protein-tyrosine kinase receptor Flk-1
Function / homology
Function and homology information


blood vessel endothelial cell differentiation / cellular response to hydrogen sulfide / regulation of bone development / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / vascular endothelial growth factor binding / Neurophilin interactions with VEGF and VEGFR / endothelium development / vascular endothelial growth factor receptor-2 signaling pathway / VEGF binds to VEGFR leading to receptor dimerization / endocardium development ...blood vessel endothelial cell differentiation / cellular response to hydrogen sulfide / regulation of bone development / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / vascular endothelial growth factor binding / Neurophilin interactions with VEGF and VEGFR / endothelium development / vascular endothelial growth factor receptor-2 signaling pathway / VEGF binds to VEGFR leading to receptor dimerization / endocardium development / vascular wound healing / vascular endothelial growth factor receptor activity / regulation of hematopoietic progenitor cell differentiation / post-embryonic camera-type eye morphogenesis / endothelial cell differentiation / mesenchymal cell proliferation / positive regulation of vasculogenesis / lymph vessel development / positive regulation of BMP signaling pathway / surfactant homeostasis / cell migration involved in sprouting angiogenesis / anchoring junction / epithelial cell maturation / positive regulation of positive chemotaxis / embryonic hemopoiesis / vascular endothelial growth factor signaling pathway / positive regulation of endothelial cell chemotaxis / positive regulation of mesenchymal cell proliferation / positive regulation of mitochondrial depolarization / branching involved in blood vessel morphogenesis / positive regulation of cell migration involved in sprouting angiogenesis / positive regulation of mitochondrial fission / lung alveolus development / positive regulation of stem cell proliferation / positive regulation of nitric-oxide synthase biosynthetic process / sorting endosome / growth factor binding / positive regulation of focal adhesion assembly / regulation of MAPK cascade / semaphorin-plexin signaling pathway / positive regulation of macroautophagy / : / positive regulation of blood vessel endothelial cell migration / cellular response to vascular endothelial growth factor stimulus / cell fate commitment / calcium ion homeostasis / Integrin cell surface interactions / vasculogenesis / vascular endothelial growth factor receptor signaling pathway / coreceptor activity / negative regulation of endothelial cell apoptotic process / peptidyl-tyrosine autophosphorylation / ovarian follicle development / positive regulation of endothelial cell proliferation / transmembrane receptor protein tyrosine kinase activity / positive regulation of endothelial cell migration / VEGFR2 mediated cell proliferation / epithelial cell proliferation / stem cell proliferation / cell surface receptor protein tyrosine kinase signaling pathway / Hsp90 protein binding / receptor protein-tyrosine kinase / VEGFA-VEGFR2 Pathway / peptidyl-tyrosine phosphorylation / positive regulation of angiogenesis / cell migration / integrin binding / cell junction / regulation of cell shape / protein tyrosine kinase activity / angiogenesis / negative regulation of neuron apoptotic process / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / early endosome / positive regulation of ERK1 and ERK2 cascade / receptor complex / endosome / positive regulation of cell migration / cadherin binding / membrane raft / positive regulation of protein phosphorylation / external side of plasma membrane / negative regulation of gene expression / positive regulation of cell population proliferation / negative regulation of apoptotic process / Golgi apparatus / endoplasmic reticulum / extracellular region / ATP binding / identical protein binding / nucleus / plasma membrane
Similarity search - Function
Vascular endothelial growth factor receptor 2 (VEGFR2) / VEGFR-2, transmembrane domain / VEGFR-2 Transmembrane domain / Vascular endothelial growth factor receptor 1-like, Ig-like domain / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin domain / Immunoglobulin / Immunoglobulin domain / Immunoglobulin I-set ...Vascular endothelial growth factor receptor 2 (VEGFR2) / VEGFR-2, transmembrane domain / VEGFR-2 Transmembrane domain / Vascular endothelial growth factor receptor 1-like, Ig-like domain / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin domain / Immunoglobulin / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / 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 / 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-GIG / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsNolte, R.T. / Wang, L.
CitationJournal: J.Med.Chem. / Year: 2007
Title: Discovery of Novel Benzimidazoles as Potent Inhibitors of TIE-2 and VEGFR-2 Tyrosine Kinase Receptors.
Authors: Hasegawa, M. / Nishigaki, N. / Washio, Y. / Kano, K. / Harris, P.A. / Sato, H. / Mori, I. / West, R.I. / Shibahara, M. / Toyoda, H. / Wang, L. / Nolte, R.T. / Veal, J.M. / Cheung, M.
History
DepositionJan 9, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 18, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Jun 14, 2017Group: Advisory / Database references ...Advisory / Database references / Source and taxonomy / Structure summary
Category: entity_name_com / entity_src_gen ...entity_name_com / entity_src_gen / pdbx_unobs_or_zero_occ_residues / struct_keywords / struct_ref_seq / struct_ref_seq_dif
Item: _entity_name_com.name / _pdbx_unobs_or_zero_occ_residues.auth_seq_id ..._entity_name_com.name / _pdbx_unobs_or_zero_occ_residues.auth_seq_id / _struct_keywords.text / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.seq_align_beg
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.4Aug 30, 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_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,1044
Polymers36,4091
Non-polymers6963
Water3,747208
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.370, 94.250, 95.754
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Vascular endothelial growth factor receptor 2 / VEGF receptor / VEGFR-2 / Fetal liver kinase 1 / FLK-1 / Kinase insert domain receptor / KDR / Protein-tyrosine ...VEGFR-2 / Fetal liver kinase 1 / FLK-1 / Kinase insert domain receptor / KDR / Protein-tyrosine kinase receptor flk-1


Mass: 36408.680 Da / Num. of mol.: 1 / Fragment: kinase domain / Mutation: E990V, Deletion of residues 940-989
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDR, FLK1, VEGFR2 / Production host: Escherichia coli (E. coli)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-GIG / METHYL (5-{4-[({[2-FLUORO-5-(TRIFLUOROMETHYL)PHENYL]AMINO}CARBONYL)AMINO]PHENOXY}-1H-BENZIMIDAZOL-2-YL)CARBAMATE


Mass: 503.406 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H17F4N5O4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 208 / 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: 2.5 Å3/Da / Density % sol: 51.1 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: pH 7.2, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Feb 1, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.05→47.67 Å / Num. obs: 22437 / % possible obs: 99.49 % / Redundancy: 6.7 % / Rmerge(I) obs: 0.064 / Χ2: 1.645 / Net I/σ(I): 24.6
Reflection shellResolution: 2.05→2.12 Å / Rmerge(I) obs: 0.179 / Mean I/σ(I) obs: 2.029 / Num. unique all: 2089 / Χ2: 0.957 / % possible all: 93.6

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT2data extraction
MAR345data collection
HKL-2000data reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1YWN

1ywn


Resolution: 2.05→47.67 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.934 / SU B: 7.332 / SU ML: 0.108 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.191 / ESU R Free: 0.168 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.231 726 3.2 %RANDOM
Rwork0.187 ---
obs0.189 22437 99.49 %-
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: 44.66 Å2
Baniso -1Baniso -2Baniso -3
1--0.17 Å20 Å20 Å2
2--1.58 Å20 Å2
3----1.42 Å2
Refinement stepCycle: LAST / Resolution: 2.05→47.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2378 0 46 208 2632
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222515
X-RAY DIFFRACTIONr_bond_other_d0.0010.021716
X-RAY DIFFRACTIONr_angle_refined_deg1.1631.993416
X-RAY DIFFRACTIONr_angle_other_deg0.87834161
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7055305
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.39223.182110
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.01915422
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.7761518
X-RAY DIFFRACTIONr_chiral_restr0.0750.2362
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022770
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02522
X-RAY DIFFRACTIONr_nbd_refined0.2180.2502
X-RAY DIFFRACTIONr_nbd_other0.190.21813
X-RAY DIFFRACTIONr_nbtor_refined0.1810.21237
X-RAY DIFFRACTIONr_nbtor_other0.0830.21216
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1590.2156
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0920.28
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1890.225
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1220.213
X-RAY DIFFRACTIONr_mcbond_it0.721.51577
X-RAY DIFFRACTIONr_mcbond_other0.1441.5610
X-RAY DIFFRACTIONr_mcangle_it1.14122435
X-RAY DIFFRACTIONr_scbond_it1.50931113
X-RAY DIFFRACTIONr_scangle_it2.334.5981
LS refinement shellResolution: 2.05→2.103 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.206 48 -
Rwork0.186 1525 -
obs-1573 95.62 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.03180.38440.18844.04010.21994.35640.06480.08810.0374-0.0414-0.03570.26270.1103-0.1636-0.0291-0.1823-0.01620.0008-0.2247-0.0125-0.22662.11834.2236.18
22.13940.33710.57652.60081.12655.2449-0.0314-0.2041-0.02260.0828-0.1230.1690.1537-0.61610.1544-0.2583-0.02410.003-0.1306-0.0344-0.26057.68441.43132.389
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Selection: ALL / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDAuth seq-IDLabel seq-ID
11817 - 92015 - 118
22921 - 1166119 - 313

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