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- PDB-9xmm: Cryo-EM structure of Integrin alpha V beta 6 complex with a bicyc... -

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Basic information

Entry
Database: PDB / ID: 9xmm
TitleCryo-EM structure of Integrin alpha V beta 6 complex with a bicyclic inhibitory peptide
Components
  • ALA-TRP-ARG-GLY-ASP-CHG-CYS-ASN-PRO
  • Integrin alpha-V heavy chain
  • Integrin beta-6
KeywordsCELL ADHESION / Integrin / Complex / Bicyclic peptide
Function / homology
Function and homology information


integrin alphav-beta8 complex / integrin alphav-beta6 complex / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / transforming growth factor beta production / opsonin binding / integrin alphav-beta1 complex / Cross-presentation of particulate exogenous antigens (phagosomes) / extracellular matrix protein binding / amelogenesis ...integrin alphav-beta8 complex / integrin alphav-beta6 complex / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / transforming growth factor beta production / opsonin binding / integrin alphav-beta1 complex / Cross-presentation of particulate exogenous antigens (phagosomes) / extracellular matrix protein binding / amelogenesis / Laminin interactions / integrin alphav-beta3 complex / negative regulation of lipoprotein metabolic process / alphav-beta3 integrin-PKCalpha complex / positive regulation of small GTPase mediated signal transduction / alphav-beta3 integrin-HMGB1 complex / entry into host cell by a symbiont-containing vacuole / negative regulation of lipid transport / regulation of phagocytosis / Elastic fibre formation / alphav-beta3 integrin-IGF-1-IGF1R complex / transforming growth factor beta binding / filopodium membrane / extracellular matrix binding / apolipoprotein A-I-mediated signaling pathway / negative regulation of low-density lipoprotein particle clearance / apoptotic cell clearance / wound healing, spreading of epidermal cells / integrin complex / Molecules associated with elastic fibres / heterotypic cell-cell adhesion / cell adhesion mediated by integrin / endodermal cell differentiation / negative chemotaxis / positive regulation of osteoblast proliferation / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / Syndecan interactions / cell-substrate adhesion / microvillus membrane / PECAM1 interactions / vasculogenesis / TGF-beta receptor signaling activates SMADs / fibronectin binding / lamellipodium membrane / positive regulation of intracellular signal transduction / ERK1 and ERK2 cascade / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / intercalated disc / Integrin cell surface interactions / ECM proteoglycans / substrate adhesion-dependent cell spreading / cell-matrix adhesion / specific granule membrane / coreceptor activity / phagocytic vesicle / positive regulation of cell adhesion / integrin-mediated signaling pathway / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / negative regulation of extrinsic apoptotic signaling pathway / molecular function activator activity / protein kinase C binding / Signal transduction by L1 / cell-cell adhesion / VEGFA-VEGFR2 Pathway / integrin binding / ruffle membrane / calcium ion transmembrane transport / angiogenesis / cell migration / signaling receptor activity / positive regulation of cytosolic calcium ion concentration / protease binding / cell adhesion / signaling receptor complex / positive regulation of cell migration / external side of plasma membrane / focal adhesion / positive regulation of cell population proliferation / symbiont entry into host cell / Neutrophil degranulation / cell surface / extracellular exosome / membrane / plasma membrane
Similarity search - Function
Integrin beta, epidermal growth factor-like domain 1 / Integrin beta epidermal growth factor like domain 1 / Integrin beta subunit, cytoplasmic domain / : / Integrin beta tail domain / Integrin beta cytoplasmic domain / Integrin alpha Ig-like domain 3 / Integrin_b_cyt / : / Integrin EGF domain ...Integrin beta, epidermal growth factor-like domain 1 / Integrin beta epidermal growth factor like domain 1 / Integrin beta subunit, cytoplasmic domain / : / Integrin beta tail domain / Integrin beta cytoplasmic domain / Integrin alpha Ig-like domain 3 / 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 / Integrin alpha cytoplasmic region / : / 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 / EGF-like domain signature 1. / EGF-like domain signature 2. / von Willebrand factor A-like domain superfamily
Similarity search - Domain/homology
alpha-D-mannopyranose / : / Integrin alpha-V / Integrin beta-6
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.88 Å
AuthorsWang, J.C. / An, Y.N.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32571409 China
CitationJournal: Angew Chem Int Ed Engl / Year: 2026
Title: Ansamer-Controlled Bicyclic Peptides as Integrin αvβ6 Targeting Agents.
Authors: Haijian Yang / Wenyan Dong / Yana An / Zhanyu He / Hui Pan / Wencong Pan / Jianhui Tan / Jingjing Sun / Chuan Shen / Wu Su / Jianchuan Wang / Roderich D Süssmuth / Guiyang Yao /
Abstract: Bicyclic peptides are promising candidates for peptide-drug conjugates due to their structural rigidity and high target specificity. Recently, it became more apparent that some peptides form ...Bicyclic peptides are promising candidates for peptide-drug conjugates due to their structural rigidity and high target specificity. Recently, it became more apparent that some peptides form nonclassical conformational isomers, termed ansamers. These conformational isomers designated as P and M are non-interconvertible and separable, thus broaden the chemical space of the peptide template. In this study, we incorporated the RGD motif into a bicyclic peptide and systematically assessed the inhibitory activities of the P and M isomers against various integrins. The molecule 10-M exhibited high selectivity and potent inhibitory activity against the αvβ6 integrin, whereas 10-P, its conformational counterpart, lacked such activity. The cryo-EM structure of αvβ6 bound to 10-M shows, that it adopts a conformation with the cyclohexane sidechain of the amino acid Chg engaging in hydrophobic interactions with Ile183 and the disulfide bond within the β6 SDL2 loop. Compared to the linear peptide A20FMDV, a broadly applied αvβ6 inhibitor, 10-M displays faster cellular internalization and also sustains prolonged enrichment within tumor tissues. Moreover, employing 10-M a designed toxin-drug conjugate exhibits remarkable tumor-suppressing effects in vivo. These findings reveal how conformational isomers of ansamers affect biological activity-and highlight their potential for the identification of new bioactive molecules.
History
DepositionNov 11, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Apr 15, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Integrin alpha-V heavy chain
B: Integrin beta-6
E: ALA-TRP-ARG-GLY-ASP-CHG-CYS-ASN-PRO
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,34914
Polymers118,4503
Non-polymers1,90011
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, SDS-PAGE
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Integrin alpha-V heavy chain


Mass: 65410.348 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The M400 of wild type integrin alpha v was substituted with a glycine and followed by an inserted extra cysteine.
Source: (gene. exp.) Homo sapiens (human) / Gene: ITGAV, MSK8, VNRA, VTNR / Plasmid: pcDNA3.4 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P06756
#2: Protein Integrin beta-6


Mass: 51981.070 Da / Num. of mol.: 1 / Mutation: I270C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ITGB6 / Plasmid: pcDNA3.4 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P18564

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Protein/peptide , 1 types, 1 molecules E

#3: Protein/peptide ALA-TRP-ARG-GLY-ASP-CHG-CYS-ASN-PRO


Mass: 1058.192 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Sugars , 4 types, 4 molecules

#4: 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.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
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
#5: 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
#7: 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
#8: Sugar ChemComp-MAN / alpha-D-mannopyranose / alpha-D-mannose / D-mannose / mannose


Type: D-saccharide, alpha linking / Mass: 180.156 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H12O6
IdentifierTypeProgram
DManpaCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
a-D-mannopyranoseCOMMON NAMEGMML 1.0
a-D-ManpIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
ManSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 7 molecules

#6: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: Ca
#9: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mn

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Details

Has ligand of interestY
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: Complex of integrin alpha v beta 6 with a bicyclic peptide.
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.12 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5 / Details: pH7.5, contains 0.2 mM CaCl2 and 1 mM MnCl2.
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNacl1
220 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidHepes1
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in.
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Tecnai Polara / Image courtesy: FEI Company
MicroscopyModel: FEI POLARA 300
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: DIFFRACTION / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 0.572 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC5particle selection
7PHENIXmodel fitting
12cryoSPARC3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 273385 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model building

3D fitting-ID: 1 / Accession code: 5FFO / Initial refinement model-ID: 1 / PDB-ID: 5FFO

5ffo

/ Source name: PDB / Type: experimental model

IDPdb chain-IDChain-IDChain residue rangePdb chain residue range
1AA1-4421-442
2BB113-353113-353

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