[English] 日本語
Yorodumi
- PDB-6xvk: Crystal structure of the KDR (VEGFR2) kinase domain in complex wi... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 6xvk
TitleCrystal structure of the KDR (VEGFR2) kinase domain in complex with a type-II inhibitor bearing an acrylamide
ComponentsVascular endothelial growth factor receptor 2
KeywordsSIGNALING PROTEIN / type II kinase inhibitor / structure-based drug design
Function / homology
Function and homology information


positive regulation of nitric oxide-cGMP mediated signal transduction / blood vessel endothelial cell differentiation / cellular response to hydrogen sulfide / regulation of bone development / 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 / cellular response to hydrogen sulfide / regulation of bone development / 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 / regulation of hematopoietic progenitor cell differentiation / post-embryonic camera-type eye morphogenesis / lymph vessel development / mesenchymal cell proliferation / positive regulation of vasculogenesis / endothelial cell differentiation / 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 / anchoring junction / embryonic hemopoiesis / vascular endothelial growth factor signaling pathway / positive regulation of mesenchymal cell proliferation / positive regulation of cell migration involved in sprouting angiogenesis / positive regulation of mitochondrial fission / branching involved in blood vessel morphogenesis / lung alveolus development / positive regulation of mitochondrial depolarization / positive regulation of stem cell proliferation / growth factor binding / 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 focal adhesion assembly / cell fate commitment / positive regulation of blood vessel endothelial cell migration / Integrin cell surface interactions / vascular endothelial growth factor receptor signaling pathway / negative regulation of endothelial cell apoptotic process / vasculogenesis / peptidyl-tyrosine autophosphorylation / calcium ion homeostasis / coreceptor activity / ovarian follicle development / 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 / VEGFR2 mediated cell proliferation / epithelial cell proliferation / stem cell proliferation / Hsp90 protein binding / 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 / peptidyl-tyrosine phosphorylation / VEGFA-VEGFR2 Pathway / positive regulation of angiogenesis / integrin binding / cell junction / cell migration / regulation of cell shape / positive regulation of protein phosphorylation / protein autophosphorylation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / protein tyrosine kinase activity / angiogenesis / negative regulation of neuron apoptotic process / early endosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of ERK1 and ERK2 cascade / positive regulation of MAPK cascade / endosome / positive regulation of cell migration / cadherin binding / membrane raft / external side of plasma membrane / negative regulation of gene expression
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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / 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 / Transferase(Phosphotransferase); domain 1 / 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-O3E / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.99 Å
AuthorsSchimpl, M. / McAuley, K. / Hoyt, E.A. / Thomas, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. ...Schimpl, M. / McAuley, K. / Hoyt, E.A. / Thomas, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. / Ward, R.A. / Kettle, J.G. / Waring, M.J.
CitationJournal: J.Am.Chem.Soc. / Year: 2020
Title: Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors.
Authors: McAulay, K. / Hoyt, E.A. / Thomas, M. / Schimpl, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Bhavsar, D. / Robinson, D.M. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. / Ward, R.A. / ...Authors: McAulay, K. / Hoyt, E.A. / Thomas, M. / Schimpl, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Bhavsar, D. / Robinson, D.M. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. / Ward, R.A. / Waring, M.J. / Kettle, J.G.
History
DepositionJan 22, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 27, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 17, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2May 1, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

-
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)37,5262
Polymers36,9901
Non-polymers5371
Water59433
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.550, 57.010, 59.890
Angle α, β, γ (deg.)90.000, 109.730, 90.000
Int Tables number4
Space group name H-MP1211

-
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


Mass: 36989.609 Da / Num. of mol.: 1 / Fragment: protein kinase domain (807-1171 del[940-989]) / Mutation: E990V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDR, FLK1, VEGFR2 / Plasmid: pFastBac1 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-O3E / ~{N}-(4,4-dimethyl-2-prop-1-ynyl-3,1-benzoxazin-6-yl)-2-[3-methoxy-5-(7-methoxyquinolin-4-yl)oxy-pyridin-2-yl]ethanamide


Mass: 536.578 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H28N4O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 33 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

-
Experimental details

-
Experiment

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

-
Sample preparation

CrystalDensity Matthews: 2.24 Å3/Da / Density % sol: 45.08 % / Mosaicity: 0.34 °
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5 / Details: 11 % PEG8000, 0.1 M PCTP buffer pH 6.5

-
Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.9801 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 30, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9801 Å / Relative weight: 1
ReflectionResolution: 1.98→48.52 Å / Num. obs: 22301 / % possible obs: 98.1 % / Redundancy: 3.4 % / Biso Wilson estimate: 55.34 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.035 / Rpim(I) all: 0.023 / Rrim(I) all: 0.042 / Net I/σ(I): 13.5 / Num. measured all: 75115 / Scaling rejects: 1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.98-2.043.21.285447813930.3950.8311.5360.784.6
8.88-48.523.10.0158552740.9990.010.01844.398.2

-
Phasing

PhasingMethod: molecular replacement

-
Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.7.4data scaling
AMoREphasing
BUSTERrefinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 1.99→48.52 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.93 / SU R Cruickshank DPI: 0.183 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.177 / SU Rfree Blow DPI: 0.157 / SU Rfree Cruickshank DPI: 0.162
RfactorNum. reflection% reflectionSelection details
Rfree0.244 1115 5 %RANDOM
Rwork0.206 ---
obs0.208 22292 98 %-
Displacement parametersBiso max: 186.92 Å2 / Biso mean: 75.99 Å2 / Biso min: 36.99 Å2
Baniso -1Baniso -2Baniso -3
1--0.6828 Å20 Å26.3129 Å2
2--0.6206 Å20 Å2
3---0.0622 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: final / Resolution: 1.99→48.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2390 0 40 33 2463
Biso mean--47.52 59.68 -
Num. residues----298
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d875SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes411HARMONIC5
X-RAY DIFFRACTIONt_it2494HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion307SEMIHARMONIC5
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_contact2847SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2494HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg3374HARMONIC20.99
X-RAY DIFFRACTIONt_omega_torsion2.9
X-RAY DIFFRACTIONt_other_torsion19.25
LS refinement shellResolution: 1.99→2.01 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.1882 22 4.93 %
Rwork0.2463 424 -
all0.2435 446 -
obs--65.54 %
Refinement TLS params.Method: refined / Origin x: -5.7405 Å / Origin y: -0.0332 Å / Origin z: 15.6195 Å
111213212223313233
T-0.221 Å20.0301 Å2-0.004 Å2--0.1953 Å2-0.0128 Å2---0.2593 Å2
L2.9145 °20.3097 °22.2612 °2-3.454 °22.144 °2--6.4769 °2
S0.0692 Å °-0.0681 Å °-0.1256 Å °-0.092 Å °-0.2419 Å °-0.0242 Å °-0.1655 Å °-0.6026 Å °0.1727 Å °
Refinement TLS groupSelection details: { A|* }

+
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