[English] 日本語
Yorodumi
- PDB-4ag8: CRYSTAL STRUCTURE OF THE VEGFR2 KINASE DOMAIN IN COMPLEX WITH AXI... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 4ag8
TitleCRYSTAL STRUCTURE OF THE VEGFR2 KINASE DOMAIN IN COMPLEX WITH AXITINIB (AG-013736) (N-Methyl-2-(3-((E)-2-pyridin-2-yl-vinyl)-1H- indazol-6-ylsulfanyl)-benzamide)
ComponentsVASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2
KeywordsTRANSFERASE / ANGIOGENESIS / NUCLEOTIDE-BINDING / INHIBITOR / PHOSPHORYLATION / TRANSMEMBRANE
Function / homology
Function and homology information


positive regulation of nitric oxide-cGMP mediated signal transduction / blood vessel endothelial cell differentiation / regulation of bone development / cellular response to hydrogen sulfide / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / Neurophilin interactions with VEGF and VEGFR / vascular endothelial growth factor binding / vascular endothelial growth factor receptor-2 signaling pathway / endothelium development / VEGF binds to VEGFR leading to receptor dimerization ...positive regulation of nitric oxide-cGMP mediated signal transduction / blood vessel endothelial cell differentiation / regulation of bone development / cellular response to hydrogen sulfide / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / Neurophilin interactions with VEGF and VEGFR / vascular endothelial growth factor binding / vascular endothelial growth factor receptor-2 signaling pathway / endothelium development / VEGF binds to VEGFR leading to receptor dimerization / endocardium development / vascular wound healing / vascular endothelial growth factor receptor activity / endothelial cell differentiation / regulation of hematopoietic progenitor cell differentiation / post-embryonic camera-type eye morphogenesis / lymph vessel development / mesenchymal cell proliferation / positive regulation of vasculogenesis / positive regulation of BMP signaling pathway / surfactant homeostasis / cell migration involved in sprouting angiogenesis / epithelial cell maturation / positive regulation of positive chemotaxis / positive regulation of endothelial cell chemotaxis / positive regulation of cell migration involved in sprouting angiogenesis / embryonic hemopoiesis / positive regulation of mesenchymal cell proliferation / anchoring junction / vascular endothelial growth factor signaling pathway / lung alveolus development / growth factor binding / positive regulation of mitochondrial fission / branching involved in blood vessel morphogenesis / positive regulation of stem cell proliferation / positive regulation of mitochondrial depolarization / sorting endosome / semaphorin-plexin signaling pathway / regulation of MAPK cascade / positive regulation of macroautophagy / cellular response to vascular endothelial growth factor stimulus / positive regulation of blood vessel endothelial cell migration / positive regulation of focal adhesion assembly / cell fate commitment / vascular endothelial growth factor receptor signaling pathway / Integrin cell surface interactions / negative regulation of endothelial cell apoptotic process / vasculogenesis / calcium ion homeostasis / ovarian follicle development / coreceptor activity / positive regulation of endothelial cell proliferation / transmembrane receptor protein tyrosine kinase activity / positive regulation of endothelial cell migration / cell surface receptor protein tyrosine kinase signaling pathway / peptidyl-tyrosine phosphorylation / VEGFR2 mediated cell proliferation / epithelial cell proliferation / stem cell proliferation / Hsp90 protein binding / receptor protein-tyrosine kinase / VEGFA-VEGFR2 Pathway / integrin binding / positive regulation of protein phosphorylation / positive regulation of angiogenesis / cell junction / cell migration / regulation of cell shape / protein autophosphorylation / protein tyrosine kinase activity / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / angiogenesis / negative regulation of neuron apoptotic process / early endosome / positive regulation of ERK1 and ERK2 cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome / positive regulation of MAPK cascade / positive regulation of cell migration / cadherin binding / membrane raft / negative regulation of gene expression / external side of plasma membrane / positive regulation of cell population proliferation / endoplasmic reticulum / Golgi apparatus / 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 / VEGFR1-3, N-terminal Ig-like domain / VEGFR-1-like, immunoglobulin-like domain / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. ...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 / VEGFR1-3, N-terminal Ig-like domain / VEGFR-1-like, immunoglobulin-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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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
AXITINIB / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsMcTigue, M. / Wickersham, J. / Pinko, C. / Kania, R.S. / Bender, S.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2012
Title: Molecular Conformations, Interactions, and Properties Associated with Drug Efficiency and Clinical Performance Among Vegfr Tk Inhibitors.
Authors: Mctigue, M. / Murray, B.W. / Chen, J.H. / Deng, Y. / Solowiej, J. / Kania, R.S.
History
DepositionJan 24, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 26, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 14, 2012Group: Database references / Other
Revision 1.2Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.3May 8, 2019Group: Data collection / Experimental preparation
Category: database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow
Item: _exptl_crystal_grow.method
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
Revision 1.5Aug 7, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 ..._chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _chem_comp_bond.value_order

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,5812
Polymers36,1951
Non-polymers3861
Water5,873326
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)135.660, 57.221, 51.829
Angle α, β, γ (deg.)90.00, 93.44, 90.00
Int Tables number5
Space group name H-MC121

-
Components

#1: Protein VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2 / 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 / CD309


Mass: 36194.762 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 806-940,990-1171 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PACSG2 / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-AXI / AXITINIB / N-METHYL-2-(3-((E)-2-PYRIDIN-2-YL-VINYL)-1H-INDAZOL-6-YLSULFANYL)-BENZAMIDE


Mass: 386.470 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H18N4OS
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 326 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, GLU 990 TO VAL

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 2.87 Å3/Da / Density % sol: 57.14 % / Description: NONE
Crystal growMethod: vapor diffusion, hanging drop / pH: 7.5
Details: CRYSTALS WERE GROWN AT 4 OR 13 C BY THE HANGING DROP VAPOR DIFFUSION BY MIXING 2 MICORLITERS OF PROTEIN-INHIBITOR COMPLEX SOLUTION WITH 2 MICROLITERS OF MOTHER LIQUOR (100 MM HEPES (PH 7.5), ...Details: CRYSTALS WERE GROWN AT 4 OR 13 C BY THE HANGING DROP VAPOR DIFFUSION BY MIXING 2 MICORLITERS OF PROTEIN-INHIBITOR COMPLEX SOLUTION WITH 2 MICROLITERS OF MOTHER LIQUOR (100 MM HEPES (PH 7.5), 200 MM AMMONIUM SULFATE, 5% (V/V) MPD, AND 15-20% (W/V) POLYETHYLENE GLYCOL (MW = 6000)). BEFORE SEALING THE COVERSLIPS ABOVE THE RESERVOIRS, BETA-MERCAPTOETHANOL WAS ADDED TO THE RESERVOIRS TO A FINAL CONCENTRATION OF 60 MM. THIS PROCEDURE PRODUCED MICROCRYSTALS THAT WERE SUBSEQUENTLY USED TO SEED MORE CRYSTALLIZATION DROPS AFTER 12-18 HOURS OF EQUILIBRATION.

-
Data collection

DiffractionMean temperature: 87 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Dec 12, 1999 / Details: MIRRORS
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.95→20 Å / Num. obs: 28556 / % possible obs: 99 % / Observed criterion σ(I): 2 / Redundancy: 2.7 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 23
Reflection shellResolution: 1.95→2.02 Å / Rmerge(I) obs: 0.18 / Mean I/σ(I) obs: 7.7 / % possible all: 97.7

-
Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
DENZOdata reduction
SCALEPACKdata scaling
EPMRphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1VR2

1vr2


Resolution: 1.95→19.84 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.914 / SU B: 3.01 / SU ML: 0.09 / Cross valid method: THROUGHOUT / ESU R: 0.16 / ESU R Free: 0.153 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.2415 1450 5.1 %RANDOM
Rwork0.19493 ---
obs0.19726 27105 98.75 %-
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: 25.15 Å2
Baniso -1Baniso -2Baniso -3
1-0.21 Å20 Å2-0.34 Å2
2--0.03 Å20 Å2
3----0.28 Å2
Refinement stepCycle: LAST / Resolution: 1.95→19.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2381 0 28 326 2735
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0212471
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1041.973337
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4395294
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0890.2355
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021872
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1870.21171
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1370.2264
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1990.238
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1360.214
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.581.51473
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.13322373
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.6713998
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.8184.5964
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: 1.953→2.003 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.249 98
Rwork0.192 1874

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more