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- PDB-9b9k: Integrin alpha-5 beta-1 in complex with MINT1526A Fab -

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Basic information

Entry
Database: PDB / ID: 9b9k
TitleIntegrin alpha-5 beta-1 in complex with MINT1526A Fab
Components
  • (MINT1526A Fab ...) x 2
  • Integrin alpha-5 light chain
  • Integrin beta-1
KeywordsSIGNALING PROTEIN / Integrin / Antibody Fab / Inhibitory
Function / homology
Function and homology information


integrin alpha8-beta1 complex / 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 / myoblast fate specification / integrin alpha9-beta1 complex ...integrin alpha8-beta1 complex / 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 / myoblast fate specification / integrin alpha9-beta1 complex / regulation of collagen catabolic process / cardiac cell fate specification / integrin alpha1-beta1 complex / integrin binding involved in cell-matrix adhesion / integrin alpha4-beta1 complex / cell-cell adhesion mediated by integrin / collagen binding involved in cell-matrix adhesion / integrin alpha2-beta1 complex / reactive gliosis / Localization of the PINCH-ILK-PARVIN complex to focal adhesions / formation of radial glial scaffolds / Other semaphorin interactions / cerebellar climbing fiber to Purkinje cell synapse / Formation of the ureteric bud / myelin sheath abaxonal region / CD40 signaling pathway / calcium-independent cell-matrix adhesion / Fibronectin matrix formation / positive regulation of fibroblast growth factor receptor signaling pathway / regulation of synapse pruning / integrin alphav-beta1 complex / CHL1 interactions / basement membrane organization / RUNX2 regulates genes involved in cell migration / cardiac muscle cell myoblast differentiation / MET interacts with TNS proteins / alphav-beta3 integrin-vitronectin complex / Laminin interactions / cardiac muscle cell differentiation / Platelet Adhesion to exposed collagen / germ cell migration / leukocyte tethering or rolling / vascular endothelial growth factor receptor 2 binding / cell projection organization / myoblast fusion / positive regulation of vascular endothelial growth factor signaling pathway / Elastic fibre formation / mesodermal cell differentiation / cell-substrate junction assembly / platelet-derived growth factor receptor binding / myoblast differentiation / axon extension / cell migration involved in sprouting angiogenesis / Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin / positive regulation of vascular endothelial growth factor receptor signaling pathway / central nervous system neuron differentiation / positive regulation of cell-substrate adhesion / regulation of spontaneous synaptic transmission / heterophilic cell-cell adhesion / wound healing, spreading of epidermal cells / epidermal growth factor receptor binding / positive regulation of fibroblast migration / integrin complex / lamellipodium assembly / sarcomere organization / heterotypic cell-cell adhesion / MET activates PTK2 signaling / Basigin interactions / Molecules associated with elastic fibres / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / negative regulation of vasoconstriction / leukocyte cell-cell adhesion / muscle organ development / Syndecan interactions / cell adhesion mediated by integrin / positive regulation of wound healing / dendrite morphogenesis / negative regulation of neuron differentiation / positive regulation of neuroblast proliferation / negative regulation of Rho protein signal transduction / response to muscle activity / maintenance of blood-brain barrier / positive regulation of sprouting angiogenesis / cell-substrate adhesion / homophilic cell-cell adhesion / endodermal cell differentiation / TGF-beta receptor signaling activates SMADs / cleavage furrow / establishment of mitotic spindle orientation / fibronectin binding / negative regulation of anoikis / intercalated disc / cellular response to low-density lipoprotein particle stimulus / positive regulation of GTPase activity / RHOG GTPase cycle / glial cell projection / neuroblast proliferation / RAC2 GTPase cycle / RAC3 GTPase cycle / ECM proteoglycans
Similarity search - Function
Integrin beta, epidermal growth factor-like domain 1 / Integrin beta epidermal growth factor like domain 1 / Integrin beta tail domain / Integrin beta subunit, cytoplasmic domain / Integrin beta cytoplasmic domain / Integrin_b_cyt / : / Integrin alpha Ig-like domain 3 / Integrin EGF domain / Integrin beta subunit, tail ...Integrin beta, epidermal growth factor-like domain 1 / Integrin beta epidermal growth factor like domain 1 / Integrin beta tail domain / Integrin beta subunit, cytoplasmic domain / Integrin beta cytoplasmic domain / Integrin_b_cyt / : / Integrin alpha Ig-like domain 3 / Integrin EGF domain / Integrin beta subunit, tail / Integrin beta tail domain superfamily / Integrin_B_tail / EGF-like domain, extracellular / EGF-like domain / 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 alpha, N-terminal / Integrin domain superfamily / PSI domain / domain found in Plexins, Semaphorins and Integrins / von Willebrand factor A-like domain superfamily / EGF-like domain signature 1.
Similarity search - Domain/homology
Integrin beta-1 / Integrin alpha-5
Similarity search - Component
Biological speciesHomo sapiens (human)
unidentified (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsNguyen, A. / Azumaya, C.M. / Campbell, M.G.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM147414-01 United States
The Pew Charitable TrustsNA United States
Other privateP30 CA015704-40
CitationJournal: bioRxiv / Year: 2025
Title: Shared ligand-blocking mechanism but distinct conformational modulation by α5-targeting antibodies BIIG2 and MINT1526A.
Authors: Adam Nguyen / Joel B Heim / Gabriele Cordara / Matthew C Chan / Hedda Johannesen / Cristine Charlesworth / Ming Li / Caleigh M Azumaya / Benjamin Madden / Ute Krengel / Alexander Meves / Melody G Campbell /
Abstract: Integrins are heterodimeric receptors important for cell adhesion and signaling. Integrin α5β1 is a key mediator of angiogenesis and its dysregulation is associated with tumor progression and ...Integrins are heterodimeric receptors important for cell adhesion and signaling. Integrin α5β1 is a key mediator of angiogenesis and its dysregulation is associated with tumor progression and metastasis. Despite numerous efforts, α5β1-targeting therapeutics have been unsuccessful due to poor efficacy and off-target effects. A contributing factor is our limited understanding of how integrin conformation influences interactions with therapeutics. Using cell-based functional assays, patient derived xenografts, biophysics, and electron microscopy, we shed light on these relationships by characterizing two anti-α5β1 antibodies, BIIG2 and MINT1526A. We show that both antibodies bind α5β1 with nanomolar affinity, reduce angiogenesis , and bind overlapping epitopes that block fibronectin binding. However, using cryoEM, we reveal that while BIIG2 binding doesn't alter the conformational states, MINT1526A restricts α5β1's range of flexibility. These insights can guide which aspects to prioritize and improve the design of future integrin-targeted therapeutics.
History
DepositionApr 2, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 5, 2025Provider: repository / Type: Initial release
Revision 1.1Oct 22, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.title / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Integrin alpha-5 light chain
B: Integrin beta-1
H: MINT1526A Fab Heavy Chain
L: MINT1526A Fab Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)221,25322
Polymers214,7244
Non-polymers6,52918
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Integrin alpha-5 light chain


Mass: 108693.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Integrin alpha-5 ectodomain with cleaved linker, HRV 3C cute site, acid coil and Strep-Tag II.
Source: (gene. exp.) Homo sapiens (human) / Gene: ITGA5, FNRA / Cell line (production host): ExpiCHO / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P08648
#2: Protein Integrin beta-1 / Fibronectin receptor subunit beta / Glycoprotein IIa / GPIIA / VLA-4 subunit beta


Mass: 80653.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Integrin beta-1 ectodomain with cleaved linker, HRV 3C cut site, base coil, and 6x His-tag.
Source: (gene. exp.) Homo sapiens (human) / Gene: ITGB1, FNRB, MDF2, MSK12 / Cell line (production host): ExpiCHO / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P05556

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Antibody , 2 types, 2 molecules HL

#3: Antibody MINT1526A Fab Heavy Chain


Mass: 13398.053 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) unidentified (others)
#4: Antibody MINT1526A Fab Light Chain


Mass: 11978.021 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) unidentified (others)

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Sugars , 5 types, 11 molecules

#5: Polysaccharide
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#6: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-6)-[alpha-D- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1235.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpa1-6[DManpa1-3]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,7,6/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3-3/a4-b1_b4-c1_c3-d1_c6-e1_e3-f1_e6-g1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#7: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#8: 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.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#10: 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.: 1 / Source method: obtained synthetically / 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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Non-polymers , 1 types, 7 molecules

#9: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Formula: Ca

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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Protein complex of integrin alpha-5 beta-1 with MINT1526A Fab
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMTris hydrochlorideTris-HCl1
2150 mMsodium chlorideNaCl1
35 mMcalcium chlorideCaCl21
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 36000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 1400 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3079

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2SerialEMimage acquisition
4cryoSPARCCTF correction
7PHENIXmodel fitting
8UCSF ChimeraXmodel fitting
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
13cryoSPARC3D reconstruction
14PHENIXmodel refinement
15ISOLDEmodel refinement
16Cootmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1339328
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 342608 / Symmetry type: POINT
Atomic model buildingB value: 106.4 / Protocol: RIGID BODY FIT / Space: REAL / Target criteria: Cross-correlation coefficient
Details: Initial local fitting was done using ChimeraX and then Phenix, ISOLDE and COOT for flexible fitting and modeling.
Atomic model building

3D fitting-ID: 1 / Accession code: 7NXD / Initial refinement model-ID: 1 / PDB-ID: 7NXD

7nxd

/ Source name: PDB / Type: experimental model

IDPdb chain-IDChain-ID
1AA
2BB
RefinementHighest resolution: 2.7 Å

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