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- EMDB-71324: Cryo-EM structure of human integrin alpha5beta1 in complex with f... -

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Entry
Database: EMDB / ID: EMD-71324
TitleCryo-EM structure of human integrin alpha5beta1 in complex with fibronectin (FN 7-10)
Map dataCryo-EM map from Refine3D
Sample
  • Complex: integrin a5b1-fibronectin complex
    • Protein or peptide: Integrin alpha-5
    • Protein or peptide: Integrin beta-1
    • Protein or peptide: Fibronectin
  • Ligand: MANGANESE (II) ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: water
Keywordsa5b1 integrin / fibronectin / extracellular matrix / focal adhesion / single-particle / cell adhesion
Function / homology
Function and homology information


integrin alpha8-beta1 complex / myoblast fate specification / integrin alpha3-beta1 complex / integrin alpha5-beta1 complex / integrin alpha6-beta1 complex / integrin alpha7-beta1 complex / integrin alpha10-beta1 complex / integrin alpha11-beta1 complex / positive regulation of glutamate uptake involved in transmission of nerve impulse / integrin alpha9-beta1 complex ...integrin alpha8-beta1 complex / myoblast fate specification / integrin alpha3-beta1 complex / integrin alpha5-beta1 complex / integrin alpha6-beta1 complex / integrin alpha7-beta1 complex / integrin alpha10-beta1 complex / integrin alpha11-beta1 complex / positive regulation of glutamate uptake involved in transmission of nerve impulse / integrin alpha9-beta1 complex / cardiac cell fate specification / regulation of collagen catabolic process / cell adhesion receptor activity / integrin alpha1-beta1 complex / integrin binding involved in cell-matrix adhesion / integrin alpha4-beta1 complex / collagen binding involved in cell-matrix adhesion / integrin alpha2-beta1 complex / Localization of the PINCH-ILK-PARVIN complex to focal adhesions / cell-cell adhesion mediated by integrin / formation of radial glial scaffolds / negative regulation of monocyte activation / Other semaphorin interactions / Formation of the ureteric bud / negative regulation of transforming growth factor beta production / cerebellar climbing fiber to Purkinje cell synapse / positive regulation of substrate-dependent cell migration, cell attachment to substrate / CD40 signaling pathway / calcium-independent cell-matrix adhesion / neural crest cell migration involved in autonomic nervous system development / reactive gliosis / positive regulation of fibroblast growth factor receptor signaling pathway / myelin sheath abaxonal region / integrin alphav-beta1 complex / CHL1 interactions / regulation of synapse pruning / fibrinogen complex / basement membrane organization / cardiac muscle cell myoblast differentiation / RUNX2 regulates genes involved in cell migration / Fibronectin matrix formation / Attachment of bacteria to epithelial cells / alphav-beta3 integrin-vitronectin complex / MET interacts with TNS proteins / Laminin interactions / enteric nervous system development / Developmental Lineage of Mammary Stem Cells / Platelet Adhesion to exposed collagen / integrin activation / germ cell migration / leukocyte tethering or rolling / vascular endothelial growth factor receptor 2 binding / ALK mutants bind TKIs / cell migration involved in sprouting angiogenesis / positive regulation of vascular endothelial growth factor signaling pathway / myoblast fusion / positive regulation of cell-substrate adhesion / cardiac muscle cell differentiation / Elastic fibre formation / cell-substrate junction assembly / axon extension / platelet-derived growth factor receptor binding / myoblast differentiation / mesodermal cell differentiation / central nervous system neuron differentiation / Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin / cell projection organization / proteoglycan binding / positive regulation of vascular endothelial growth factor receptor signaling pathway / wound healing, spreading of epidermal cells / heterophilic cell-cell adhesion / positive regulation of fibroblast migration / regulation of spontaneous synaptic transmission / integrin complex / cell adhesion mediated by integrin / negative regulation of Rho protein signal transduction / Molecules associated with elastic fibres / MET activates PTK2 signaling / heterotypic cell-cell adhesion / Basigin interactions / epidermal growth factor receptor binding / lamellipodium assembly / peptidase activator activity / neural crest cell migration / negative regulation of vasoconstriction / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / muscle organ development / sarcomere organization / Syndecan interactions / extracellular matrix structural constituent / leukocyte cell-cell adhesion / biological process involved in interaction with symbiont / p130Cas linkage to MAPK signaling for integrins / dendrite morphogenesis / positive regulation of neuroblast proliferation / positive regulation of wound healing / negative regulation of neuron differentiation / response to muscle activity / positive regulation of sprouting angiogenesis / regulation of protein phosphorylation
Similarity search - Function
Fibronectin type I domain / Fibronectin, type I / Fibronectin type-I domain signature. / Fibronectin type-I domain profile. / Fibronectin type 1 domain / : / Fibronectin type II domain / Fibronectin type II domain superfamily / Fibronectin type II domain / Fibronectin type-II collagen-binding domain signature. ...Fibronectin type I domain / Fibronectin, type I / Fibronectin type-I domain signature. / Fibronectin type-I domain profile. / Fibronectin type 1 domain / : / Fibronectin type II domain / Fibronectin type II domain superfamily / Fibronectin type II domain / Fibronectin type-II collagen-binding domain signature. / Fibronectin type-II collagen-binding domain profile. / Fibronectin type 2 domain / Integrin beta, epidermal growth factor-like domain 1 / Integrin beta epidermal growth factor like domain 1 / : / Integrin alpha Ig-like domain 3 / Integrin beta subunit, cytoplasmic domain / Integrin beta tail domain / Integrin beta cytoplasmic domain / Integrin_b_cyt / : / Integrin EGF domain / EGF-like domain, extracellular / EGF-like domain / Integrin beta subunit, tail / Integrin beta tail domain superfamily / Integrin_B_tail / : / Integrins beta chain EGF (I-EGF) domain profile. / Integrin beta subunit, VWA domain / Integrin beta subunit / Integrin beta N-terminal / Integrin beta chain VWA domain / Integrin plexin domain / Integrins beta chain EGF (I-EGF) domain signature. / Integrin beta subunits (N-terminal portion of extracellular region) / Integrin alpha-2 / Integrin alpha Ig-like domain 1 / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / Integrins alpha chain signature. / Integrin alpha chain / Integrin alpha beta-propellor / : / Integrin alpha Ig-like domain 2 / FG-GAP repeat profile. / Integrin alpha (beta-propellor repeats). / FG-GAP repeat / FG-GAP repeat / Integrin domain superfamily / Integrin alpha, N-terminal / PSI domain / domain found in Plexins, Semaphorins and Integrins / Kringle-like fold / Fibronectin type III domain / von Willebrand factor A-like domain superfamily / EGF-like domain signature 1. / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Fibronectin / Integrin beta-1 / Integrin alpha-5
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.61 Å
AuthorsDing J / Fantini D / Dedden D / Schumacher S / Biertumpfel C / Mizuno N
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)1ZIAHL006264 United States
CitationJournal: PNAS Nexus / Year: 2026
Title: Allosteric regulation of fibronectin binding by the anti-β1 integrin antibody TS2/16.
Authors: Jienyu Ding / Dalia A Fantini / Dirk Dedden / Stephanie Schumacher / Christian Biertümpfel / Naoko Mizuno /
Abstract: The monoclonal antibody (mAb) TS2/16 stabilizes the active conformation of β1 integrin, enhancing its adhesive capacity on the cell surface. However, the molecular mechanism by which TS2/16 ...The monoclonal antibody (mAb) TS2/16 stabilizes the active conformation of β1 integrin, enhancing its adhesive capacity on the cell surface. However, the molecular mechanism by which TS2/16 modulates integrin affinity for extracellular ligands remains unclear. Using endogenous full-length α5β1 integrin purified from human placenta, we determined the structure of integrin α5β1 with fibronectin up to 2.61-Å resolution in the absence of TS2/16, capturing the active form without its aid, and performed comparative B-factor-based analysis and CABS-Flex simulation with and without TS2/16. Despite no global conformational differences, we found that TS2/16 interacts with α2 helix of the integrin β1 subunit and contacts the C-terminus of α3 helix, leading to a localized decrease in B factor. This interaction allosterically alters the dynamics of α2-α3 loop despite not being in direct contact with TS2/16. Notably, this loop directly engages fibronectin, and its dynamic change underlies the enhanced ligand-binding affinity and explains increased cell adhesion observed with TS2/16. These findings reveal an allosteric mechanism of integrin regulation by TS2/16 and offer insights for the rational design of therapeutic antibodies targeting integrin-mediated adhesion in pathological contexts such as inflammation and cancer.
History
DepositionJun 19, 2025-
Header (metadata) releaseMar 25, 2026-
Map releaseMar 25, 2026-
UpdateMar 25, 2026-
Current statusMar 25, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71324.png

Downloads & links

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Map

FileDownload / File: emd_71324.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM map from Refine3D
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 480 pix.
= 407.773 Å		0.85 Å/pix.
x 480 pix.
= 407.773 Å		0.85 Å/pix.
x 480 pix.
= 407.773 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.84953 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.012
Minimum - Maximum-0.019948632 - 0.07100111
Average (Standard dev.)0.000011946075 (±0.0011031051)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 407.77335 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_71324_msk_1.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Additional map: Cryo-EM map from PostProcess, masked

Fileemd_71324_additional_1.map
AnnotationCryo-EM map from PostProcess, masked
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: Half map B from Refine3D

Fileemd_71324_half_map_1.map
AnnotationHalf map B from Refine3D
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Half map: Half map A from Refine3D

Fileemd_71324_half_map_2.map
AnnotationHalf map A from Refine3D
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Sample components

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Entire : integrin a5b1-fibronectin complex

EntireName: integrin a5b1-fibronectin complex
Components
  • Complex: integrin a5b1-fibronectin complex
    • Protein or peptide: Integrin alpha-5
    • Protein or peptide: Integrin beta-1
    • Protein or peptide: Fibronectin
  • Ligand: MANGANESE (II) ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: water

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Supramolecule #1: integrin a5b1-fibronectin complex

SupramoleculeName: integrin a5b1-fibronectin complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human) / Organ: placenta

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Macromolecule #1: Integrin alpha-5

MacromoleculeName: Integrin alpha-5 / type: protein_or_peptide / ID: 1 / Details: processed (signal peptide is cleaved) / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Organ: placenta
Molecular weightTheoretical: 64.73377 KDa
SequenceString: FNLDAEAPAV LSGPPGSFFG FSVEFYRPGT DGVSVLVGAP KANTSQPGVL QGGAVYLCPW GASPTQCTPI EFDSKGSRLL ESSLSSSEG EEPVEYKSLQ WFGATVRAHG SSILACAPLY SWRTEKEPLS DPVGTCYLST DNFTRILEYA PCRSDFSWAA G QGYCQGGF ...String:
FNLDAEAPAV LSGPPGSFFG FSVEFYRPGT DGVSVLVGAP KANTSQPGVL QGGAVYLCPW GASPTQCTPI EFDSKGSRLL ESSLSSSEG EEPVEYKSLQ WFGATVRAHG SSILACAPLY SWRTEKEPLS DPVGTCYLST DNFTRILEYA PCRSDFSWAA G QGYCQGGF SAEFTKTGRV VLGGPGSYFW QGQILSATQE QIAESYYPEY LINLVQGQLQ TRQASSIYDD SYLGYSVAVG EF SGDDTED FVAGVPKGNL TYGYVTILNG SDIRSLYNFS GEQMASYFGY AVAATDVNGD GLDDLLVGAP LLMDRTPDGR PQE VGRVYV YLQHPAGIEP TPTLTLTGHD EFGRFGSSLT PLGDLDQDGY NDVAIGAPFG GETQQGVVFV FPGGPGGLGS KPSQ VLQPL WAASHTPDFF GSALRGGRDL DGNGYPDLIV GSFGVDKAVV YRGRPIVSAS ASLTIFPAMF NPEERSCSLE GNPVA CINL SFCLNASGKH VADSIGFTVE LQLDWQKQKG GVRRALFLAS RQATLTQTLL IQNGAREDCR EMKIYLRNES EFRDKL SPI HIALNFSLDP QAPVDSHGLR PALHYQSKSR IEDKAQIL

UniProtKB: Integrin alpha-5

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Macromolecule #2: Integrin beta-1

MacromoleculeName: Integrin beta-1 / type: protein_or_peptide / ID: 2 / Details: processed (signal peptide is cleaved) / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Organ: placenta
Molecular weightTheoretical: 48.952363 KDa
SequenceString: RCLKANAKSC GECIQAGPNC GWCTNSTFLQ EGMPTSARCD DLEALKKKGC PPDDIENPRG SKDIKKNKNV TNRSKGTAEK LKPEDIHQI QPQQLVLRLR SGEPQTFTLK FKRAEDYPID LYYLMDLSYS MKDDLENVKS LGTDLMNEMR RITSDFRIGF G SFVEKTVM ...String:
RCLKANAKSC GECIQAGPNC GWCTNSTFLQ EGMPTSARCD DLEALKKKGC PPDDIENPRG SKDIKKNKNV TNRSKGTAEK LKPEDIHQI QPQQLVLRLR SGEPQTFTLK FKRAEDYPID LYYLMDLSYS MKDDLENVKS LGTDLMNEMR RITSDFRIGF G SFVEKTVM PYISTTPAKL RNPCTSEQNC TTPFSYKNVL SLTNKGEVFN ELVGKQRISG NLDSPEGGFD AIMQVAVCGS LI GWRNVTR LLVFSTDAGF HFAGDGKLGG IVLPNDGQCH LENNMYTMSH YYDYPSIAHL VQKLSENNIQ TIFAVTEEFQ PVY KELKNL IPKSAVGTLS ANSSNVIQLI IDAYNSLSSE VILENGKLSE GVTISYKSYC KNGVNGTGEN GRKCSNISIG DEVQ FEISI TSNKCPKKDS DSFKIRPLGF TEEVEVILQY ICECE

UniProtKB: Integrin beta-1

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Macromolecule #3: Fibronectin

MacromoleculeName: Fibronectin / type: protein_or_peptide / ID: 3 / Details: truncated to domains FN7-10 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 19.849061 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
LDSPTGIDFS DITANSFTVH WIAPRATITG YRIRHHPEHF SGRPREDRVP HSRNSITLTN LTPGTEYVVS IVALNGREES PLLIGQQST VSDVPRDLEV VAATPTSLLI SWDAPAVTVR YYRITYGETG GNSPVQEFTV PGSKSTATIS GLKPGVDYTI T VYAVTGRG DSPASSKPIS INYRT

UniProtKB: Fibronectin

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Macromolecule #8: MANGANESE (II) ION

MacromoleculeName: MANGANESE (II) ION / type: ligand / ID: 8 / Number of copies: 7 / Formula: MN
Molecular weightTheoretical: 54.938 Da

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Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 9 / Number of copies: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Macromolecule #10: water

MacromoleculeName: water / type: ligand / ID: 10 / Number of copies: 27 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration1.9 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 3.8000000000000003 kPa
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
Detailsintegrin a5b1 in nanodiscs (MSPE3D1) was incubated with 10 mM MnCl2 for 30 min at 4C, then mixed with purified FN7-10 at a molar ratio of 1:3, at a final a5b1-ND concentration of 0.15 mg/ml in TBS pH 7.5 and 1 mM MnCl2.

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
SoftwareName: SerialEM
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 10341 / Average electron dose: 69.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.62 mm / Nominal defocus max: 3.2 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2640989
CTF correctionSoftware - Name: RELION (ver. 3.0) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.61 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 130907
Initial angle assignmentType: OTHER / Software - Name: RELION (ver. 3.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0)
Final 3D classificationNumber classes: 4 / Software - Name: RELION
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

3vi3

source_name: PDB, initial_model_type: experimental model

1fnf

residue_range: 1327-1509, source_name: PDB, initial_model_type: experimental model
SoftwareName: Coot
Detailsinitial rigid body fitting in chimera, then cycles of manual adjustment/modeling in coot and real-space refinement in phenix
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-9p6s:
Cryo-EM structure of human integrin alpha5beta1 in complex with fibronectin (FN 7-10)

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