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- EMDB-75407: Dimeric complex of VEGF, VEGFR2 and Neuropilin 1 -

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Entry
Database: EMDB / ID: EMD-75407
TitleDimeric complex of VEGF, VEGFR2 and Neuropilin 1
Map data
Sample
  • Complex: dimeric complex of VEGF, VEGFR2 and Neuropilin 1
    • Protein or peptide: Isoform VEGF-1 of Vascular endothelial growth factor A, long form
    • Protein or peptide: Vascular endothelial growth factor receptor 2
    • Protein or peptide: Neuropilin-1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
KeywordsVEGF / VEGFR / neuropilin / SIGNALING PROTEIN
Function / homology
Function and homology information


positive regulation of lymphangiogenesis / VEGF-A complex / VEGF ligand-receptor interactions / VEGF binds to VEGFR leading to receptor dimerization / blood vessel endothelial cell differentiation / Neuropilin interactions with VEGF and VEGFR / bone trabecula formation / post-embryonic camera-type eye morphogenesis / cell migration involved in coronary vasculogenesis / trigeminal nerve morphogenesis ...positive regulation of lymphangiogenesis / VEGF-A complex / VEGF ligand-receptor interactions / VEGF binds to VEGFR leading to receptor dimerization / blood vessel endothelial cell differentiation / Neuropilin interactions with VEGF and VEGFR / bone trabecula formation / post-embryonic camera-type eye morphogenesis / cell migration involved in coronary vasculogenesis / trigeminal nerve morphogenesis / VEGFR2 mediated cell proliferation / Signal transduction by L1 / dichotomous subdivision of terminal units involved in salivary gland branching / regulation of bone development / regulation of hematopoietic progenitor cell differentiation / regulation of axon extension involved in axon guidance / regulation of endothelial cell differentiation / negative regulation of axon extension involved in axon guidance / basal dendrite development / otic placode development / CRMPs in Sema3A signaling / Sema3A PAK dependent Axon repulsion / basal dendrite arborization / regulation of endothelial cell proliferation / positive regulation of smooth muscle cell chemotaxis / retina vasculature morphogenesis in camera-type eye / vestibulocochlear nerve structural organization / dorsal root ganglion morphogenesis / lymphangiogenesis / ventral trunk neural crest cell migration / sympathetic neuron projection guidance / facioacoustic ganglion development / trigeminal ganglion development / sensory neuron axon guidance / basophil chemotaxis / lymph vessel morphogenesis / positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway / positive regulation of nitric oxide-cGMP mediated signal transduction / cellular stress response to acid chemical / : / facial nerve structural organization / trigeminal nerve structural organization / branchiomotor neuron axon guidance / vascular endothelial growth factor receptor 1 binding / negative regulation of adherens junction organization / gonadotrophin-releasing hormone neuronal migration to the hypothalamus / protein localization to early endosome / post-embryonic camera-type eye development / primitive erythrocyte differentiation / retina vasculature development in camera-type eye / positive regulation of mast cell chemotaxis / negative regulation of establishment of endothelial barrier / vascular endothelial growth factor receptor binding / negative regulation of blood-brain barrier permeability / lung vasculature development / VEGF-activated neuropilin signaling pathway / axon extension involved in axon guidance / positive regulation of cell proliferation by VEGF-activated platelet derived growth factor receptor signaling pathway / motor neuron migration / eye photoreceptor cell development / renal artery morphogenesis / SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion / positive regulation of signal transduction / cellular response to hydrogen sulfide / endothelium development / endochondral bone growth / coronary vein morphogenesis / cardiac vascular smooth muscle cell development / lymph vessel development / neurofilament / regulation of vascular endothelial growth factor receptor signaling pathway / sympathetic neuron projection extension / mammary gland alveolus development / endocardium development / angiogenesis involved in coronary vascular morphogenesis / postsynapse organization / vascular endothelial growth factor binding / endothelial cell differentiation / vascular endothelial growth factor receptor-2 signaling pathway / endothelial tube morphogenesis / sympathetic ganglion development / negative regulation of axon extension / neural crest cell migration involved in autonomic nervous system development / axonogenesis involved in innervation / bone trabecula morphogenesis / vascular endothelial growth factor receptor activity / positive regulation of axon extension involved in axon guidance / endothelial cell chemotaxis / camera-type eye morphogenesis / positive regulation of protein localization to early endosome / Platelet degranulation / positive regulation of trophoblast cell migration / surfactant homeostasis / positive regulation of long-term neuronal synaptic plasticity / sympathetic nervous system development / retinal ganglion cell axon guidance / positive regulation of vasculogenesis / induction of positive chemotaxis / vascular wound healing / dopaminergic neuron differentiation
Similarity search - Function
Neuropilin / Neuropilin, C-terminal / C-terminal domain of neuropilin glycoprotein / Vascular endothelial growth factor receptor 2 (VEGFR2) / Vascular endothelial growth factor, heparin-binding domain / Vascular endothelial growth factor, heparin-binding domain superfamily / VEGF heparin-binding domain / VEGFR-2, transmembrane domain / : / VEGFR-2 Transmembrane domain ...Neuropilin / Neuropilin, C-terminal / C-terminal domain of neuropilin glycoprotein / Vascular endothelial growth factor receptor 2 (VEGFR2) / Vascular endothelial growth factor, heparin-binding domain / Vascular endothelial growth factor, heparin-binding domain superfamily / VEGF heparin-binding domain / 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 / MAM domain signature. / : / VEGFR1-3, N-terminal Ig-like domain / Domain in meprin, A5, receptor protein tyrosine phosphatase mu (and others) / : / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Coagulation factors 5/8 type C domain (FA58C) signature 2. / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Coagulation factors 5/8 type C domain (FA58C) signature 1. / CUB domain / Domain first found in C1r, C1s, uEGF, and bone morphogenetic protein. / CUB domain / Spermadhesin, CUB domain superfamily / CUB domain profile. / Coagulation factor 5/8 C-terminal domain, discoidin domain / Coagulation factors 5/8 type C domain (FA58C) profile. / F5/8 type C domain / Coagulation factor 5/8 C-terminal domain / Cystine-knot cytokine / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Galactose-binding-like domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Concanavalin A-like lectin/glucanase domain superfamily / 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 2 / Neuropilin-1 / Vascular endothelial growth factor A, long form
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsChen L / Bai X / Zhang X
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM130289 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM156386 United States
Robert A. Welch FoundationI-1702 United States
Robert A. Welch FoundationI-1944 United States
CitationJournal: Sci Adv / Year: 2026
Title: Mechanisms of VEGFR2 activation by VEGF, neuropilin, and heparin.
Authors: Lianqi Chen / Zhichen Sun / Jian Qiao / Xiao-Chen Bai / Xuewu Zhang /
Abstract: Vascular endothelial growth factor (VEGF) and its receptor VEGFR are master regulators of vasculogenesis and angiogenesis. VEGF activates VEGFR by inducing its dimerization and trans- ...Vascular endothelial growth factor (VEGF) and its receptor VEGFR are master regulators of vasculogenesis and angiogenesis. VEGF activates VEGFR by inducing its dimerization and trans-autophosphorylation. The coreceptor neuropilin (Nrp1 and Nrp2) and heparan sulfate proteoglycan (HSPG) modulate VEGF-VEGFR signaling, but the underlying mechanisms remain incompletely understood. Here we report a cryo-EM structure of the dimeric mouse VEGF-VEGFR2-Nrp1 ectodomain complex with a 2:2:2 stoichiometry, revealing direct Nrp1-VEGFR2 interactions that stabilize the VEGFR2 dimer. We also determined two cryo-EM structures of the VEGF-VEGFR2-Nrp1 complex in the presence of short- or long-chain heparin, which bridges all three proteins and promotes the formation of two distinct tetrameric complexes. Long-chain heparin induces a cis tetrameric complex consistent with receptor clustering on the same cell surface, whereas short-chain heparin promotes a trans tetrameric assembly which might be formed by two dimeric complexes from opposing cells. Our structure-based mutational analyses support the model that both the Nrp1-VEGFR2 interface and the heparin-mediated clustering enhance VEGFR2 signaling.
History
DepositionFeb 3, 2026-
Header (metadata) releaseJun 10, 2026-
Map releaseJun 10, 2026-
UpdateJul 29, 2026-
Current statusJul 29, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_75407.png

Downloads & links

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Map

FileDownload / File: emd_75407.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 330 pix.
= 356.4 Å		1.08 Å/pix.
x 330 pix.
= 356.4 Å		1.08 Å/pix.
x 330 pix.
= 356.4 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.008
Minimum - Maximum-0.040489085 - 0.08620506
Average (Standard dev.)0.000099932266 (±0.0016584942)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions330330330
Spacing330330330
CellA=B=C: 356.40002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_75407_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_75407_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : dimeric complex of VEGF, VEGFR2 and Neuropilin 1

EntireName: dimeric complex of VEGF, VEGFR2 and Neuropilin 1
Components
  • Complex: dimeric complex of VEGF, VEGFR2 and Neuropilin 1
    • Protein or peptide: Isoform VEGF-1 of Vascular endothelial growth factor A, long form
    • Protein or peptide: Vascular endothelial growth factor receptor 2
    • Protein or peptide: Neuropilin-1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION

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Supramolecule #1: dimeric complex of VEGF, VEGFR2 and Neuropilin 1

SupramoleculeName: dimeric complex of VEGF, VEGFR2 and Neuropilin 1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 400 KDa

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Macromolecule #1: Isoform VEGF-1 of Vascular endothelial growth factor A, long form

MacromoleculeName: Isoform VEGF-1 of Vascular endothelial growth factor A, long form
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 20.787742 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
ELEHHHHHHH HAPTTEGEQK SHEVIKFMDV YQRSYCRPIE TLVDIFQEYP DEIEYIFKPS CVPLMRCAGC CNDEALECVP TSESNITMQ IMRIKPHQSQ HIGEMSFLQH SRCECRPKKD RTKPENHCEP CSERRKHLFV QDPQTCKCSC KNTDSRCKAR Q LELNERTC RCDKPRR

UniProtKB: Vascular endothelial growth factor A, long form

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Macromolecule #2: Vascular endothelial growth factor receptor 2

MacromoleculeName: Vascular endothelial growth factor receptor 2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 84.499039 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ELEASVGLPG DFLHPPKLST QKDILTILAN TTLQITCRGQ RDLDWLWPNA QRDSEERVLV TECGGGDSIF CKTLTIPRVV GNDTGAYKC SYRDVDIAST VYVYVRDYRS PFIASVSDQH GIVYITENKN KTVVIPCRGS ISNLNVSLCA RYPEKRFVPD G NRISWDSE ...String:
ELEASVGLPG DFLHPPKLST QKDILTILAN TTLQITCRGQ RDLDWLWPNA QRDSEERVLV TECGGGDSIF CKTLTIPRVV GNDTGAYKC SYRDVDIAST VYVYVRDYRS PFIASVSDQH GIVYITENKN KTVVIPCRGS ISNLNVSLCA RYPEKRFVPD G NRISWDSE IGFTLPSYMI SYAGMVFCEA KINDETYQSI MYIVVVVGYR IYDVILSPPH EIELSAGEKL VLNCTARTEL NV GLDFTWH SPPSKSHHKK IVNRDVKPFP GTVAKMFLST LTIESVTKSD QGEYTCVASS GRMIKRNRTF VRVHTKPFIA FGS GMKSLV EATVGSQVRI PVKYLSYPAP DIKWYRNGRP IESNYTMIVG DELTIMEVTE RDAGNYTVIL TNPISMEKQS HMVS LVVNV PPQIGEKALI SPMDSYQYGT MQTLTCTVYA NPPLHHIQWY WQLEEACSYR PGQTSPYACK EWRHVEDFQG GNKIE VTKN QYALIEGKNK TVSTLVIQAA NVSALYKCEA INKAGRGERV ISFHVIRGPE ITVQPAAQPT EQESVSLLCT ADRNTF ENL TWYKLGSQAT SVHMGESLTP VCKNLDALWK LNGTMFSNST NDILIVAFQN ASLQDQGDYV CSAQDKKTKK RHCLVKQ LI ILERMAPMIT GNLENQTTTI GETIEVTCPA SGNPTPHITW FKDNETLVED SGIVLRDGNR NLTIRRVRKE DGGLYTCQ A CNVLGCARAE TLFIIEGAQE KTNGTHHHHH HHH

UniProtKB: Vascular endothelial growth factor receptor 2

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Macromolecule #3: Neuropilin-1

MacromoleculeName: Neuropilin-1 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 95.312578 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ELEFRSDKCG GTIKIENPGY LTSPGYPHSY HPSEKCEWLI QAPEPYQRIM INFNPHFDLE DRDCKYDYVE VIDGENEGGR LWGKFCGKI APSPVVSSGP FLFIKFVSDY ETHGAGFSIR YEIFKRGPEC SQNYTAPTGV IKSPGFPEKY PNSLECTYII F APKMSEII ...String:
ELEFRSDKCG GTIKIENPGY LTSPGYPHSY HPSEKCEWLI QAPEPYQRIM INFNPHFDLE DRDCKYDYVE VIDGENEGGR LWGKFCGKI APSPVVSSGP FLFIKFVSDY ETHGAGFSIR YEIFKRGPEC SQNYTAPTGV IKSPGFPEKY PNSLECTYII F APKMSEII LEFESFDLEQ DSNPPGGMFC RYDRLEIWDG FPEVGPHIGR YCGQKTPGRI RSSSGVLSMV FYTDSAIAKE GF SANYSVL QSSISEDFKC MEALGMESGE IHSDQITASS QYGTNWSVER SRLNYPENGW TPGEDSYKEW IQVDLGLLRF VTA VGTQGA ISKETKKKYY VKTYRVDISS NGEDWISLKE GNKAIIFQGN TNPTDVVLGV FSKPLITRFV RIKPVSWETG ISMR FEVYG CKITDYPCSG MLGMVSGLIS DSQITASNQA DRNWMPENIR LVTSRTGWAL PPSPHPYTNE WLQVDLGDEK IVRGV IIQG GKHRENKVFM RKFKIAYSNN GSDWKTIMDD SKRKAKSFEG NNNYDTPELR TFSPLSTRFI RIYPERATHS GLGLRM ELL GCEVEAPTAG PTTPNGNPVD ECDDDQANCH SGTGDDFQLT GGTTVLATEK PTIIDSTIQS EFPTYGFNCE FGWGSHK TF CHWEHDSHAQ LRWSVLTSKT GPIQDHTGDG NFIYSQADEN QKGKVARLVS PVVYSQSSAH CMTFWYHMSG SHVGTLRV K LRYQKPEEYD QLVWMVVGHQ GDHWKEGRVL LHKSLKLYQV IFEGEIGKGN LGGIAVDDIS INNHISQEDC AKPTDLDKK NTEIKIDETG STPGYEGEGE GDKNISRKPG NVLKTLDGTH HHHHHHH

UniProtKB: Neuropilin-1

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #5: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 5 / Number of copies: 4 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7
VitrificationCryogen name: NITROGEN

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 64468
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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