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- EMDB-67027: Cryo-EM structure of Integrin alpha V beta 6 complex with a bicyc... -

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Entry
Database: EMDB / ID: EMD-67027
TitleCryo-EM structure of Integrin alpha V beta 6 complex with a bicyclic inhibitory peptide
Map data
Sample
  • Complex: Complex of integrin alpha v beta 6 with a bicyclic peptide.
    • Protein or peptide: Integrin alpha-V heavy chain
    • Protein or peptide: Integrin beta-6
  • Protein or peptide: ALA-TRP-ARG-GLY-ASP-CHG-CYS-ASN-PRO
  • Ligand: CALCIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: alpha-D-mannopyranose
  • Ligand: MANGANESE (II) ION
KeywordsIntegrin / Complex / Bicyclic peptide / CELL ADHESION
Function / homology
Function and homology information


memory T cell differentiation / Langerhans cell differentiation / integrin alphav-beta8 complex / integrin alphav-beta6 complex / transforming growth factor beta production / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / opsonin binding / enamel mineralization / bronchiole development ...memory T cell differentiation / Langerhans cell differentiation / integrin alphav-beta8 complex / integrin alphav-beta6 complex / transforming growth factor beta production / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / opsonin binding / enamel mineralization / bronchiole development / 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 / entry into host cell by a symbiont-containing vacuole / positive regulation of small GTPase mediated signal transduction / phospholipid homeostasis / alphav-beta3 integrin-HMGB1 complex / negative regulation of lipid transport / hard palate development / regulation of phagocytosis / Elastic fibre formation / surfactant homeostasis / alphav-beta3 integrin-IGF-1-IGF1R complex / transforming growth factor beta binding / extracellular matrix binding / filopodium membrane / apolipoprotein A-I-mediated signaling pathway / negative regulation of low-density lipoprotein particle clearance / wound healing, spreading of epidermal cells / apoptotic cell clearance / integrin complex / cell adhesion mediated by integrin / heterotypic cell-cell adhesion / Molecules associated with elastic fibres / negative chemotaxis / lung alveolus development / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / Syndecan interactions / skin development / positive regulation of osteoblast proliferation / microvillus membrane / cell-substrate adhesion / PECAM1 interactions / endodermal cell differentiation / TGF-beta receptor signaling activates SMADs / fibronectin binding / lamellipodium membrane / positive regulation of intracellular signal transduction / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / ECM proteoglycans / Integrin cell surface interactions / vasculogenesis / specific granule membrane / coreceptor activity / phagocytic vesicle / ERK1 and ERK2 cascade / extrinsic apoptotic signaling pathway in absence of ligand / substrate adhesion-dependent cell spreading / transforming growth factor beta receptor signaling pathway / positive regulation of cell adhesion / molecular function activator activity / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / protein kinase C binding / cell-matrix adhesion / negative regulation of extrinsic apoptotic signaling pathway / Signal transduction by L1 / cellular response to ionizing radiation / integrin-mediated signaling pathway / wound healing / cell-cell adhesion / bone development / VEGFA-VEGFR2 Pathway / integrin binding / calcium ion transmembrane transport / response to virus / ruffle membrane / cell morphogenesis / cell migration / virus receptor activity / positive regulation of cytosolic calcium ion concentration / signaling receptor activity / protease binding / angiogenesis / cell adhesion / signaling receptor complex / positive regulation of cell migration / inflammatory response / external side of plasma membrane / focal adhesion / positive regulation of cell population proliferation / Neutrophil degranulation / symbiont entry into host cell / cell surface / extracellular exosome
Similarity search - Function
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 ...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 / 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 / von Willebrand factor A-like domain superfamily / EGF-like domain signature 1. / EGF-like domain signature 2.
Similarity search - Domain/homology
Integrin alpha-V / Integrin beta-6
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.88 Å
AuthorsWang JC / An YN
Funding support China, 1 items
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, 2025-
Header (metadata) releaseApr 15, 2026-
Map releaseApr 15, 2026-
UpdateApr 15, 2026-
Current statusApr 15, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_67027.png

Downloads & links

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Map

FileDownload / File: emd_67027.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.57 Å/pix.
x 360 pix.
= 205.92 Å		0.57 Å/pix.
x 360 pix.
= 205.92 Å		0.57 Å/pix.
x 360 pix.
= 205.92 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.572 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.091541335 - 0.17074767
Average (Standard dev.)-0.00020006213 (±0.0048425803)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 205.92001 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_67027_additional_1.map
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Half map: #2

Fileemd_67027_half_map_1.map
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Half map: #1

Fileemd_67027_half_map_2.map
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Sample components

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Entire : Complex of integrin alpha v beta 6 with a bicyclic peptide.

EntireName: Complex of integrin alpha v beta 6 with a bicyclic peptide.
Components
  • Complex: Complex of integrin alpha v beta 6 with a bicyclic peptide.
    • Protein or peptide: Integrin alpha-V heavy chain
    • Protein or peptide: Integrin beta-6
  • Protein or peptide: ALA-TRP-ARG-GLY-ASP-CHG-CYS-ASN-PRO
  • Ligand: CALCIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: alpha-D-mannopyranose
  • Ligand: MANGANESE (II) ION

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Supramolecule #1: Complex of integrin alpha v beta 6 with a bicyclic peptide.

SupramoleculeName: Complex of integrin alpha v beta 6 with a bicyclic peptide.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 120 KDa

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Macromolecule #1: Integrin alpha-V heavy chain

MacromoleculeName: Integrin alpha-V heavy chain / type: protein_or_peptide / ID: 1
Details: The M400 of wild type integrin alpha v was substituted with a glycine and followed by an inserted extra cysteine.
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 65.410348 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: FNLDVDSPAE YSGPEGSYFG FAVDFFVPSA SSRMFLLVGA PKANTTQPGI VEGGQVLKCD WSSTRRCQPI EFDATGNRDY AKDDPLEFK SHQWFGASVR SKQDKILACA PLYHWRTEMK QEREPVGTCF LQDGTKTVEY APCRSQDIDA DGQGFCQGGF S IDFTKADR ...String:
FNLDVDSPAE YSGPEGSYFG FAVDFFVPSA SSRMFLLVGA PKANTTQPGI VEGGQVLKCD WSSTRRCQPI EFDATGNRDY AKDDPLEFK SHQWFGASVR SKQDKILACA PLYHWRTEMK QEREPVGTCF LQDGTKTVEY APCRSQDIDA DGQGFCQGGF S IDFTKADR VLLGGPGSFY WQGQLISDQV AEIVSKYDPN VYSIKYNNQL ATRTAQAIFD DSYLGYSVAV GDFNGDGIDD FV SGVPRAA RTLGMVYIYD GKNMSSLYNF TGEQMAAYFG FSVAATDING DDYADVFIGA PLFMDRGSDG KLQEVGQVSV SLQ RASGDF QTTKLNGFEV FARFGSAIAP LGDLDQDGFN DIAIAAPYGG EDKKGIVYIF NGRSTGLNAV PSQILEGQWA ARSG CPPSF GYSMKGATDI DKNGYPDLIV GAFGVDRAIL YRARPVITVN AGLEVYPSIL NQDNKTCSLP GTALKVSCFN VRFCL KADG KGVLPRKLNF QVELLLDKLK QKGAIRRALF LYSRSPSHSK NMTISRGGLM QCEELIAYLR DESEFRDKLT PITIFM EYR LDYRTAADTT GLQPILNQFT PANISRQAHI LL

UniProtKB: Integrin alpha-V

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Macromolecule #2: Integrin beta-6

MacromoleculeName: Integrin beta-6 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 51.98107 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: HVQGGCALGG AETCEDCLLI GPQCAWCAQE NFTHPSGVGE RCDTPANLLA KGCQLNFIEN PVSQVEILKN KPLSVGRQKN SSDIVQIAP QSLILKLRPG GAQTLQVHVR QTEDYPVDLY YLMDLSASMD DDLNTIKELG SRLSKEMSKL TSNFRLGFGS F VEKPVSPF ...String:
HVQGGCALGG AETCEDCLLI GPQCAWCAQE NFTHPSGVGE RCDTPANLLA KGCQLNFIEN PVSQVEILKN KPLSVGRQKN SSDIVQIAP QSLILKLRPG GAQTLQVHVR QTEDYPVDLY YLMDLSASMD DDLNTIKELG SRLSKEMSKL TSNFRLGFGS F VEKPVSPF VKTTPEEIAN PCSSIPYFCL PTFGFKHILP LTNDAERFNE IVKNQKISAN IDTPEGGFDA IMQAAVCKEK IG WRNDSLH LLVFVSDADS HFGMDSKLAG IVCPNDGLCH LDSKNEYSMS TVLEYPTIGQ LIDKLVQNNV LLIFAVTQEQ VHL YENYAK LIPGATVGLL QKDSGNILQL IISAYEELRS EVELEVLGDT EGLNLSFTAI CNNGTLFQHQ KKCSHMKVGD TASF SVTVN IPHCERRSRH IIIKPVGLGD ALELLVSPEC NCDCQKEVEV NSSKCHHGNG SFQCGVCACH PGHMGPRCE

UniProtKB: Integrin beta-6

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Macromolecule #3: ALA-TRP-ARG-GLY-ASP-CHG-CYS-ASN-PRO

MacromoleculeName: ALA-TRP-ARG-GLY-ASP-CHG-CYS-ASN-PRO / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 1.058192 KDa
SequenceString:
AWRGD(CHG)CNP

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Macromolecule #6: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 6 / Number of copies: 4 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Macromolecule #8: alpha-D-mannopyranose

MacromoleculeName: alpha-D-mannopyranose / type: ligand / ID: 8 / Number of copies: 1 / Formula: MAN
Molecular weightTheoretical: 180.156 Da
Chemical component information

ChemComp-MAN:
alpha-D-mannopyranose

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Macromolecule #9: MANGANESE (II) ION

MacromoleculeName: MANGANESE (II) ION / type: ligand / ID: 9 / Number of copies: 3 / Formula: MN
Molecular weightTheoretical: 54.938 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

Concentration1.0 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
150.0 mMNaclsodium chloride
20.0 mMHepes4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

Details: pH7.5, contains 0.2 mM CaCl2 and 1 mM MnCl2.
GridMaterial: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI POLARA 300
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 0.572 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Tecnai Polara / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 273385
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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Atomic model buiding 1

Initial model
PDB IDChain

5ffo

chain_id: A, residue_range: 1-442, source_name: PDB, initial_model_type: experimental model

5ffo

chain_id: B, residue_range: 113-353, source_name: PDB, initial_model_type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9xmm:
Cryo-EM structure of Integrin alpha V beta 6 complex with a bicyclic inhibitory peptide

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