[English] 日本語
Yorodumi
- PDB-21ei: Structural and Functional Insights into VEGFR-3-Mediated Lymphang... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 21ei
TitleStructural and Functional Insights into VEGFR-3-Mediated Lymphangiogenesis : Unraveling the clustering mechanism of VEGFR-3/VEGF-C
Components
  • Vascular endothelial growth factor C
  • Vascular endothelial growth factor receptor 3
KeywordsSIGNALING PROTEIN / VEGFR-3 / VEGF-C / cis-clustering / trans-clustering / VEGFR-3/VEGF-C signaling / receptor tyrosine kinases
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsCho, R.E. / Ahn, J.S. / Kim, H.M.
Funding support Korea, Republic Of, 2items
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, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 30, 2026Provider: repository / Type: Initial release
Revision 1.0Sep 30, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Vascular endothelial growth factor receptor 3
B: Vascular endothelial growth factor receptor 3
E: Vascular endothelial growth factor receptor 3
D: Vascular endothelial growth factor C
C: Vascular endothelial growth factor C
H: Vascular endothelial growth factor C
G: Vascular endothelial growth factor C


Theoretical massNumber of molelcules
Total (without water)317,7627
Polymers317,7627
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

-
Components

#1: Protein Vascular endothelial growth factor receptor 3 / VEGFR-3 / Fms-like tyrosine kinase 4 / FLT-4 / Tyrosine-protein kinase receptor FLT4


Mass: 87501.086 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FLT4, VEGFR3 / Cell line (production host): Expi293F / Production host: Homo sapiens (human)
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


Mass: 13814.687 Da / Num. of mol.: 4 / Mutation: C39A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VEGFC / Cell line (production host): Expi293F / Production host: Homo sapiens (human) / References: UniProt: P49767
Has protein modificationY

-
Experimental details

-
Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: 3D ARRAY / 3D reconstruction method: single particle reconstruction

-
Sample preparation

ComponentName: VEGFR-3/VEGF-C / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.101 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4 / Details: PBS
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 %

-
Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1900 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 67.3 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

-
Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21.2_5419model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 486815 / Symmetry type: POINT

+
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