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- PDB-4bsk: Crystal structure of VEGF-C in complex with VEGFR-3 domains D1-2 -

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Basic information

Entry
Database: PDB / ID: 4bsk
TitleCrystal structure of VEGF-C in complex with VEGFR-3 domains D1-2
Components
  • VASCULAR ENDOTHELIAL GROWTH FACTOR C
  • VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 3
KeywordsTRANSFERASE/HORMONE / TRANSFERASE-HORMONE COMPLEX / TRANSFERASE / LYMPHANGIOGENESIS / ANGIOGENESIS / IG DOMAIN / GLYCOPROTEIN / RECEPTOR TYROSINE KINASE / DIMERIZATION
Function / homology
Function and homology information


vascular endothelial growth factor receptor 3 binding / substrate-dependent cell migration / regulation of blood vessel remodeling / regulation of vascular endothelial growth factor receptor signaling pathway / positive regulation of lymphangiogenesis / VEGF ligand-receptor interactions / positive regulation of mast cell chemotaxis / positive regulation of protein kinase C signaling / positive regulation of mesenchymal stem cell proliferation / morphogenesis of embryonic epithelium ...vascular endothelial growth factor receptor 3 binding / substrate-dependent cell migration / regulation of blood vessel remodeling / regulation of vascular endothelial growth factor receptor signaling pathway / positive regulation of lymphangiogenesis / VEGF ligand-receptor interactions / positive regulation of mast cell chemotaxis / positive regulation of protein kinase C signaling / positive regulation of mesenchymal stem cell proliferation / morphogenesis of embryonic epithelium / lymphangiogenesis / VEGF binds to VEGFR leading to receptor dimerization / respiratory system process / vascular endothelial growth factor receptor activity / lymph vessel development / induction of positive chemotaxis / vasculature development / sprouting angiogenesis / blood vessel morphogenesis / NOTCH4 Intracellular Domain Regulates Transcription / vascular endothelial growth factor signaling pathway / positive regulation of neuroblast proliferation / lung alveolus development / chemoattractant activity / growth factor binding / regulation of MAPK cascade / positive regulation of cell division / positive regulation of vascular endothelial growth factor production / positive regulation of blood vessel endothelial cell migration / cellular response to vascular endothelial growth factor stimulus / negative regulation of osteoblast differentiation / glial cell proliferation / vascular endothelial growth factor receptor signaling pathway / positive regulation of glial cell proliferation / positive regulation of protein autophosphorylation / positive regulation of endothelial cell proliferation / cell surface receptor protein tyrosine kinase signaling pathway / negative regulation of blood pressure / positive regulation of endothelial cell migration / transmembrane receptor protein tyrosine kinase activity / platelet alpha granule lumen / cellular response to leukemia inhibitory factor / positive regulation of protein secretion / animal organ morphogenesis / positive regulation of JNK cascade / growth factor activity / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / positive regulation of angiogenesis / Platelet degranulation / protein phosphatase binding / angiogenesis / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of ERK1 and ERK2 cascade / receptor complex / response to hypoxia / positive regulation of cell migration / response to xenobiotic stimulus / positive regulation of protein phosphorylation / positive regulation of cell population proliferation / negative regulation of apoptotic process / signal transduction / protein homodimerization activity / extracellular space / extracellular region / nucleoplasm / ATP binding / membrane / plasma membrane / cytosol
Similarity search - Function
CXCXC repeat / CXCXC repeat / VEGFR-2, transmembrane domain / VEGFR-2 Transmembrane domain / Vascular endothelial growth factor receptor 1-like, Ig-like domain / PDGF/VEGF domain / Platelet-derived growth factor, conserved site / PDGF/VEGF domain / Platelet-derived growth factor (PDGF) family signature. / Platelet-derived growth factor (PDGF) family profile. ...CXCXC repeat / CXCXC repeat / VEGFR-2, transmembrane domain / VEGFR-2 Transmembrane domain / Vascular endothelial growth factor receptor 1-like, Ig-like domain / PDGF/VEGF domain / Platelet-derived growth factor, conserved site / PDGF/VEGF domain / Platelet-derived growth factor (PDGF) family signature. / Platelet-derived growth factor (PDGF) family profile. / Platelet-derived and vascular endothelial growth factors (PDGF, VEGF) family / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Cystine-knot cytokine / 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 / 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
Similarity search - Domain/homology
Vascular endothelial growth factor receptor 3 / Vascular endothelial growth factor C
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MIRAS / Resolution: 4.201 Å
AuthorsLeppanen, V.M. / Tvorogov, D. / Kisko, K. / Prota, A.E. / Jeltsch, M. / Anisimov, A. / Markovic-Mueller, S. / Stuttfeld, E. / Goldie, K.N. / Ballmer-Hofer, K. / Alitalo, K.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2013
Title: Structural and Mechanistic Insights Into Vegfr-3 Ligand Binding and Activation
Authors: Leppanen, V.-M. / Tvorogov, D. / Kisko, K. / Prota, A.E. / Jeltsch, M. / Anisimov, A. / Markovic-Mueller, S. / Stuttfeld, E. / Goldie, K.N. / Ballmer-Hofer, K. / Alitalo, K.
History
DepositionJun 10, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 31, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2013Group: Database references
Revision 1.2Aug 28, 2013Group: Derived calculations
Revision 2.0Apr 11, 2018Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations
Category: atom_site / database_PDB_caveat ...atom_site / database_PDB_caveat / pdbx_nonpoly_scheme / pdbx_struct_sheet_hbond / pdbx_validate_chiral / struct_conf / struct_conn / struct_sheet / struct_sheet_order / struct_sheet_range / struct_site
Item: _atom_site.auth_seq_id / _pdbx_nonpoly_scheme.pdb_seq_num ..._atom_site.auth_seq_id / _pdbx_nonpoly_scheme.pdb_seq_num / _pdbx_struct_sheet_hbond.range_1_auth_atom_id / _pdbx_struct_sheet_hbond.range_1_auth_comp_id / _pdbx_struct_sheet_hbond.range_1_auth_seq_id / _pdbx_struct_sheet_hbond.range_1_label_atom_id / _pdbx_struct_sheet_hbond.range_1_label_comp_id / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_auth_atom_id / _pdbx_struct_sheet_hbond.range_2_auth_comp_id / _pdbx_struct_sheet_hbond.range_2_auth_seq_id / _pdbx_struct_sheet_hbond.range_2_label_atom_id / _pdbx_struct_sheet_hbond.range_2_label_comp_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _pdbx_struct_sheet_hbond.sheet_id / _pdbx_validate_chiral.auth_seq_id / _struct_conf.beg_auth_comp_id / _struct_conf.beg_auth_seq_id / _struct_conf.beg_label_comp_id / _struct_conf.beg_label_seq_id / _struct_conf.pdbx_PDB_helix_id / _struct_conf.pdbx_PDB_helix_length / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry / _struct_sheet.id / _struct_sheet_order.sheet_id / _struct_sheet_range.sheet_id / _struct_site.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 2.1Apr 24, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 2.2May 8, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 3.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Other / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_database_status / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _chem_comp.name / _chem_comp.type / _pdbx_database_status.status_code_sf / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 3.1Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 3
C: VASCULAR ENDOTHELIAL GROWTH FACTOR C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7607
Polymers37,4512
Non-polymers1,3095
Water00
1
A: VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 3
C: VASCULAR ENDOTHELIAL GROWTH FACTOR C
hetero molecules

A: VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 3
C: VASCULAR ENDOTHELIAL GROWTH FACTOR C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,52114
Polymers74,9024
Non-polymers2,61810
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1,-y,z1
Buried area4080 Å2
ΔGint-35.2 kcal/mol
Surface area38280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)166.660, 166.660, 166.660
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number197
Space group name H-MI23

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Components

#1: Protein VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 3 / VEGFR-3 / FMS-LIKE TYROSINE KINASE 4 / FLT-4 / TYROSINE-PROTEIN KINASE RECEPTOR FLT4 / VEGFR-3


Mass: 23856.611 Da / Num. of mol.: 1 / Fragment: LIGAND-BINDING DOMAINS D1-2, RESIDUES 23-229
Source method: isolated from a genetically manipulated source
Details: COVALENT N-GLYCOSYLATION IN ASN33, ASN104 AND ASN166
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC1 / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P35916, receptor protein-tyrosine kinase
#2: Protein VASCULAR ENDOTHELIAL GROWTH FACTOR C / VEGF-C / FLT4 LIGAND / FLT4-L / VASCULAR ENDOTHELIAL GROWTH FACTOR-RELATED PROTEIN / VRP / VEGF-C


Mass: 13594.500 Da / Num. of mol.: 1 / Fragment: VEGF HOMOLOGY DOMAIN, RESIDUES 103-215 / Mutation: YES
Source method: isolated from a genetically manipulated source
Details: COVALENT N-GLYCOSYLATION IN ASN175 AND ASN205 / Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC1 / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P49767
#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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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: 5.2 Å3/Da / Density % sol: 72 % / Description: NONE
Crystal growMethod: vapor diffusion, sitting drop / pH: 9
Details: SITTING DROPS AT ROOM TEMPERATURE OVER A RESERVOIR SOLUTION OF 0.1 M BIS-TRIS BUFFER AT PH 8.5-9.5 AND 1.0-1.5 M AMMONIUM SULPHATE.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 8, 2011
RadiationMonochromator: LN2 COOLED FIXED-EXIT SI(111) MONOCHROMATOR / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 4.2→30 Å / Num. obs: 5765 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Redundancy: 9.9 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 20.9
Reflection shellResolution: 4.2→4.4 Å / Redundancy: 10.5 % / Rmerge(I) obs: 1.49 / Mean I/σ(I) obs: 2.1 / % possible all: 100

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Processing

Software
NameClassification
XDSdata reduction
XDSdata scaling
autoSHARPphasing
MOLREPphasing
PHENIXrefinement
RefinementMethod to determine structure: MIRAS
Starting model: PDB ENTRIES 2X1X, 1FLT AND 2E9W

2x1x

1flt

2e9w


Resolution: 4.201→19.92 Å / SU ML: 0.96 / σ(F): 2 / Phase error: 52.28 / Stereochemistry target values: MLHL
Details: RESIDUES 103-114 AND 213-215 IN VEGF-C AND RESIDUES 23-27, 77-89, 114-123, 211-212 AND 225-229 IN VEGFR-3 ARE DISORDERED. ATOMS OF DISORDERED SIDECHAINS WERE OMITTED FROM THE FINAL MODEL.
RfactorNum. reflection% reflection
Rfree0.3718 572 10 %
Rwork0.3341 --
obs0.338 5721 100 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 135.9 Å2
Refinement stepCycle: LAST / Resolution: 4.201→19.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1792 0 84 0 1876
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0041924
X-RAY DIFFRACTIONf_angle_d1.0322651
X-RAY DIFFRACTIONf_dihedral_angle_d15.257615
X-RAY DIFFRACTIONf_chiral_restr0.061337
X-RAY DIFFRACTIONf_plane_restr0.006339
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
4.2008-4.61870.43791420.39531275X-RAY DIFFRACTION100
4.6187-5.27620.4771410.42121275X-RAY DIFFRACTION100
5.2762-6.60690.45261430.44651280X-RAY DIFFRACTION100
6.6069-19.91990.32391460.27891319X-RAY DIFFRACTION100
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)
10.1414-0.27920.14140.5692-0.25820.16460.1784-0.1823-0.27640.18890.29240.17950.09550.17960.14171.1568-0.4292-0.0070.9691-0.28660.8004-91.86440.2163-14.9626
20.04090.05820.03560.04660.04250.0149-0.0916-0.08860.0569-0.0048-0.0077-0.1687-0.10480.0191-0.15940.796-0.8554-0.36020.2624-0.59380.4524-72.051532.4435-21.6582
30.04520.0392-0.05010.0406-0.04190.04930.16950.16910.09790.02150.3504-0.2343-0.08480.01090.14281.4476-0.85620.01240.7205-0.18391.3619-52.806553.2412-18.6545
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN C AND ((RESSEQ 115:213))
2X-RAY DIFFRACTION2CHAIN A AND ((RESSEQ 134:224))
3X-RAY DIFFRACTION3CHAIN A AND ((RESSEQ 28:133))

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