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- EMDB-67618: Structural and Functional Insights into VEGFR-3-Mediated Lymphang... -

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Basic information

Entry
Database: EMDB / ID: EMD-67618
TitleStructural and Functional Insights into VEGFR-3-Mediated Lymphangiogenesis : Unraveling the clustering mechanism of VEGFR-3/VEGF-C
Map data
Sample
  • Complex: VEGFR-3/VEGF-C
    • Protein or peptide: Vascular endothelial growth factor receptor 3
    • Protein or peptide: Vascular endothelial growth factor C
KeywordsVEGFR-3 / VEGF-C / cis-clustering / trans-clustering / VEGFR-3/VEGF-C signaling / receptor tyrosine kinases / SIGNALING PROTEIN
Function / homology
Function and homology information


vascular endothelial growth factor receptor 3 binding / substrate-dependent cell migration / lymphangiogenesis / regulation of blood vessel remodeling / VEGF ligand-receptor interactions / positive regulation of mast cell chemotaxis / lymph vessel development / regulation of vascular endothelial growth factor receptor signaling pathway / positive regulation of mesenchymal stem cell proliferation / VEGF binds to VEGFR leading to receptor dimerization ...vascular endothelial growth factor receptor 3 binding / substrate-dependent cell migration / lymphangiogenesis / regulation of blood vessel remodeling / VEGF ligand-receptor interactions / positive regulation of mast cell chemotaxis / lymph vessel development / regulation of vascular endothelial growth factor receptor signaling pathway / positive regulation of mesenchymal stem cell proliferation / VEGF binds to VEGFR leading to receptor dimerization / vascular endothelial growth factor receptor activity / induction of positive chemotaxis / blood vessel morphogenesis / sprouting angiogenesis / vasculature development / NOTCH4 Intracellular Domain Regulates Transcription / positive regulation of cell division / vascular endothelial growth factor signaling pathway / growth factor binding / chemoattractant activity / cellular response to vascular endothelial growth factor stimulus / positive regulation of vascular endothelial growth factor production / vascular endothelial growth factor receptor signaling pathway / positive regulation of blood vessel endothelial cell migration / negative regulation of osteoblast differentiation / negative regulation of blood pressure / positive regulation of endothelial cell proliferation / transmembrane receptor protein tyrosine kinase activity / positive regulation of epithelial cell proliferation / peptidyl-tyrosine phosphorylation / positive regulation of endothelial cell migration / platelet alpha granule lumen / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of protein secretion / growth factor activity / receptor protein-tyrosine kinase / positive regulation of JNK cascade / positive regulation of protein phosphorylation / positive regulation of angiogenesis / Platelet degranulation / protein autophosphorylation / cell migration / cell differentiation / protein phosphatase binding / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / response to hypoxia / positive regulation of MAPK cascade / positive regulation of ERK1 and ERK2 cascade / signaling receptor complex / response to xenobiotic stimulus / positive regulation of cell migration / positive regulation of cell population proliferation / negative regulation of apoptotic process / signal transduction / : / protein homodimerization activity / extracellular region / ATP binding / membrane / nucleus / 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 / VEGFR-1-like, immunoglobulin-like domain / : / PDGF/VEGF domain / Platelet-derived growth factor, conserved site ...CXCXC repeat / CXCXC repeat / VEGFR-2, transmembrane domain / : / VEGFR-2 Transmembrane domain / Vascular endothelial growth factor receptor 1-like, Ig-like domain / VEGFR-1-like, immunoglobulin-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 / : / VEGFR1-3, N-terminal Ig-like domain / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Cystine-knot cytokine / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsCho RE / Ahn JS / Kim HM
Funding support Korea, Republic Of, 2 items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)RS-2024-00397681 Korea, Republic Of
National Research Foundation (NRF, Korea)RS-2025-00523575 Korea, Republic Of
CitationJournal: Adv Sci (Weinh) / Year: 2026
Title: Structural Basis of Lymphangiogenic Receptor VEGFR-3 Activation Mediated by Distinctive Clustering of the Ligand-Receptor Complex.
Authors: Ryeongeun Cho / Jinsook Ahn / Jimin Yang / Dong Sun Lee / Gahi Hong / Sangkyu Lee / Ho Min Kim /
Abstract: Vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 are critical for lymphangiogenesis, yet the structural mechanisms beyond simple dimerization that drive activation remain ...Vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 are critical for lymphangiogenesis, yet the structural mechanisms beyond simple dimerization that drive activation remain unknown. Here, we report the first cryo-EM structure of the human VEGFR-3 full ectodomain in complex with VEGF-C. Such a canonical ligand-induced 2:2 hetero-tetrameric complex further self-assembles into distinct higher-order assemblies-a lateral cis-cluster and an inverted trans-like-cluster. Further analysis of these canonical 2:2 hetero-tetramer in higher-order assemblies identifies that the specificity of VEGF-C for VEGFR-3 and VEGFR-2 over VEGFR-1 is mainly governed by its N-terminal α1 helix, which is structurally accommodated by the D2 domains of VEGFR-3 and VEGFR-2 but sterically excluded by the protruding D1-D2 connecting loop of VEGFR-1. Furthermore, we identify a unique interface within the membrane-proximal D5 domain occurring between neighboring canonical 2:2 complexes, mediated by a specific "WTP motif," as a key driver of cis-clustering. Structure-guided mutagenesis and real-time optogenetic assays support a critical role for cis-clustering in signal amplification and show that enforced receptor clustering can drive robust activation, whereas trans-like-clustering appears dispensable. Collectively, these findings transform the traditional "monomer-to-dimer" activation model of VEGFR-3/VEGF-C into a "dimer-to-cluster" paradigm, providing a blueprint for engineering next-generation therapeutics targeting lymphatic vascular diseases.
History
DepositionDec 10, 2025-
Header (metadata) releaseSep 30, 2026-
Map releaseSep 30, 2026-
UpdateSep 30, 2026-
Current statusSep 30, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_67618.png

Downloads & links

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Map

FileDownload / File: emd_67618.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 400 pix.
= 339.2 Å		0.85 Å/pix.
x 400 pix.
= 339.2 Å		0.85 Å/pix.
x 400 pix.
= 339.2 Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.848 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0023
Minimum - Maximum-0.026131334 - 2.3410482
Average (Standard dev.)0.0007393844 (±0.014710827)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 339.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_67618_msk_1.map
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Half map: #2

Fileemd_67618_half_map_1.map
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Half map: #1

Fileemd_67618_half_map_2.map
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Sample components

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Entire : VEGFR-3/VEGF-C

EntireName: VEGFR-3/VEGF-C
Components
  • Complex: VEGFR-3/VEGF-C
    • Protein or peptide: Vascular endothelial growth factor receptor 3
    • Protein or peptide: Vascular endothelial growth factor C

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Supramolecule #1: VEGFR-3/VEGF-C

SupramoleculeName: VEGFR-3/VEGF-C / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 101 KDa

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Macromolecule #1: Vascular endothelial growth factor receptor 3

MacromoleculeName: Vascular endothelial growth factor receptor 3 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 87.501086 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MQRGAALCLR LWLCLGLLDG LVSGYSMTPP TLNITEESHV IDTGDSLSIS CRGQHPLEWA WPGAQEAPAT GDKDSEDTGV VRDCEGTDA RPYCKVLLLH EVHANDTGSY VCYYKYIKAR IEGTTAASSY VFVRDFEQPF INKPDTLLVN RKDAMWVPCL V SIPGLNVT ...String:
MQRGAALCLR LWLCLGLLDG LVSGYSMTPP TLNITEESHV IDTGDSLSIS CRGQHPLEWA WPGAQEAPAT GDKDSEDTGV VRDCEGTDA RPYCKVLLLH EVHANDTGSY VCYYKYIKAR IEGTTAASSY VFVRDFEQPF INKPDTLLVN RKDAMWVPCL V SIPGLNVT LRSQSSVLWP DGQEVVWDDR RGMLVSTPLL HDALYLQCET TWGDQDFLSN PFLVHITGNE LYDIQLLPRK SL ELLVGEK LVLNCTVWAE FNSGVTFDWD YPGKQAERGK WVPERRSQQT HTELSSILTI HNVSQHDLGS YVCKANNGIQ RFR ESTEVI VHENPFISVE WLKGPILEAT AGDELVKLPV KLAAYPPPEF QWYKDGKALS GRHSPHALVL KEVTEASTGT YTLA LWNSA AGLRRNISLE LVVNVPPQIH EKEASSPSIY SRHSRQALTC TAYGVPLPLS IQWHWRPWTP CKMFAQRSLR RRQQQ DLMP QCRDWRAVTT QDAVNPIESL DTWTEFVEGK NKTVSKLVIQ NANVSAMYKC VVSNKVGQDE RLIYFYVTTI PDGFTI ESK PSEELLEGQP VLLSCQADSY KYEHLRWYRL NLSTLHDAHG NPLLLDCKNV HLFATPLAAS LEEVAPGARH ATLSLSI PR VAPEHEGHYV CEVQDRRSHD KHCHKKYLSV QALEAPRLTQ NLTDLLVNVS DSLEMQCLVA GAHAPSIVWY KDERLLEE K SGVDLADSNQ KLSIQRVREE DAGRYLCSVC NAKGCVNSSA SVAVEGSEDL KLEVLFQ

UniProtKB: Vascular endothelial growth factor receptor 3

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Macromolecule #2: Vascular endothelial growth factor C

MacromoleculeName: Vascular endothelial growth factor C / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.814687 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
SGGSTEETIK FAAAHYNTEI LKSIDNEWRK TQCMPREVAI DVGKEFGVAT NTFFKPPCVS VYRCGGCCNS EGLQCMNTST SYLSKTLFE ITVPLSQGPK PVTISFANHT SCRCMSKLGS HHHHHH

UniProtKB: Vascular endothelial growth factor C

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation state3D array

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Sample preparation

Concentration1 mg/mL
BufferpH: 7.4 / Details: PBS
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 90 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 67.3 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.9000000000000001 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4bsj

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.5 CUT-OFF / Software - Name: cryoSPARC / Number images used: 580022
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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