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- EMDB-41153: Integrin alpha-v beta-8 in complex with minibinder B8_BP_dsulf -

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Basic information

Entry
Database: EMDB / ID: EMD-41153
TitleIntegrin alpha-v beta-8 in complex with minibinder B8_BP_dsulf
Map data
Sample
  • Complex: Ternary complex of integrin heterodimer (alpha-v beta-8) and the de novo minibinder protein B8_BP_dslf
    • Protein or peptide: Integrin alpha-V heavy chain
    • Protein or peptide: Integrin beta-8
    • Protein or peptide: Minibinder B8_BP_dslf
  • Ligand: CALCIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: MAGNESIUM ION
KeywordsComplex / heterodimer / signaling / TGF-Beta / DE NOVO PROTEIN
Function / homology
Function and homology information


ganglioside metabolic process / 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 / integrin alphav-beta1 complex / Cross-presentation of particulate exogenous antigens (phagosomes) ...ganglioside metabolic process / 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 / integrin alphav-beta1 complex / Cross-presentation of particulate exogenous antigens (phagosomes) / extracellular matrix protein binding / placenta blood vessel development / Laminin interactions / integrin alphav-beta3 complex / negative regulation of lipoprotein metabolic process / entry into host cell by a symbiont-containing vacuole / alphav-beta3 integrin-PKCalpha complex / alphav-beta3 integrin-HMGB1 complex / negative regulation of lipid transport / hard palate development / regulation of phagocytosis / Elastic fibre formation / alphav-beta3 integrin-IGF-1-IGF1R complex / transforming growth factor beta binding / positive regulation of small GTPase mediated signal transduction / filopodium membrane / cartilage development / extracellular matrix binding / negative regulation of low-density lipoprotein particle clearance / apolipoprotein A-I-mediated signaling pathway / apoptotic cell clearance / integrin complex / wound healing, spreading of epidermal cells / heterotypic cell-cell adhesion / Molecules associated with elastic fibres / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / negative chemotaxis / cell adhesion mediated by integrin / Syndecan interactions / positive regulation of osteoblast proliferation / microvillus membrane / cell-substrate adhesion / endodermal cell differentiation / PECAM1 interactions / TGF-beta receptor signaling activates SMADs / positive regulation of intracellular signal transduction / lamellipodium membrane / fibronectin binding / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / ECM proteoglycans / Integrin cell surface interactions / vasculogenesis / voltage-gated calcium channel activity / specific granule membrane / coreceptor activity / phagocytic vesicle / ERK1 and ERK2 cascade / extrinsic apoptotic signaling pathway in absence of ligand / substrate adhesion-dependent cell spreading / positive regulation of cell adhesion / transforming growth factor beta receptor signaling pathway / protein kinase C binding / cell-matrix adhesion / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / Signal transduction by L1 / integrin-mediated signaling pathway / negative regulation of extrinsic apoptotic signaling pathway / cell-cell adhesion / calcium ion transmembrane transport / VEGFA-VEGFR2 Pathway / response to virus / ruffle membrane / integrin binding / positive regulation of angiogenesis / cell migration / positive regulation of cytosolic calcium ion concentration / virus receptor activity / protease binding / angiogenesis / cell adhesion / immune response / positive regulation of cell migration / negative regulation of gene expression / external side of plasma membrane / focal adhesion / positive regulation of cell population proliferation / Neutrophil degranulation / positive regulation of gene expression / symbiont entry into host cell / cell surface / extracellular exosome / metal ion binding / membrane / plasma membrane / cytosol
Similarity search - Function
Teneurin-like EGF domain / : / Integrin alpha Ig-like domain 3 / Integrin EGF domain / 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 ...Teneurin-like EGF domain / : / Integrin alpha Ig-like domain 3 / Integrin EGF domain / 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 / Integrin alpha beta-propellor / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / : / Integrin alpha Ig-like domain 2 / Integrins alpha chain signature. / 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. / EGF-like domain signature 2. / EGF-like domain
Similarity search - Domain/homology
Integrin alpha-V / Integrin beta-8
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsCampbell MG / Fernandez A / Roy A / Kraft J / Baker D
Funding support United States, 5 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM147414 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM092802 United States
The Pew Charitable Trusts United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM008268-33 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nat Commun / Year: 2023
Title: De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8.
Authors: Anindya Roy / Lei Shi / Ashley Chang / Xianchi Dong / Andres Fernandez / John C Kraft / Jing Li / Viet Q Le / Rebecca Viazzo Winegar / Gerald Maxwell Cherf / Dean Slocum / P Daniel Poulson / ...Authors: Anindya Roy / Lei Shi / Ashley Chang / Xianchi Dong / Andres Fernandez / John C Kraft / Jing Li / Viet Q Le / Rebecca Viazzo Winegar / Gerald Maxwell Cherf / Dean Slocum / P Daniel Poulson / Garrett E Casper / Mary L Vallecillo-Zúniga / Jonard Corpuz Valdoz / Marcos C Miranda / Hua Bai / Yakov Kipnis / Audrey Olshefsky / Tanu Priya / Lauren Carter / Rashmi Ravichandran / Cameron M Chow / Max R Johnson / Suna Cheng / McKaela Smith / Catherine Overed-Sayer / Donna K Finch / David Lowe / Asim K Bera / Gustavo Matute-Bello / Timothy P Birkland / Frank DiMaio / Ganesh Raghu / Jennifer R Cochran / Lance J Stewart / Melody G Campbell / Pam M Van Ry / Timothy Springer / David Baker /
Abstract: The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between ...The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous αvβ6 and αvβ8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed. Here we describe a generalized method for computationally designing RGD-containing miniproteins selective for a single RGD integrin heterodimer and conformational state. We design hyperstable, selective αvβ6 and αvβ8 inhibitors that bind with picomolar affinity. CryoEM structures of the designed inhibitor-integrin complexes are very close to the computational design models, and show that the inhibitors stabilize specific conformational states of the αvβ6 and the αvβ8 integrins. In a lung fibrosis mouse model, the αvβ6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.
History
DepositionJun 30, 2023-
Header (metadata) releaseSep 27, 2023-
Map releaseSep 27, 2023-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Downloads & links

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Map

FileDownload / File: emd_41153.map.gz / Format: CCP4 / Size: 166.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.122 Å
Density
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-1.9612774 - 3.3482788
Average (Standard dev.)0.00013661405 (±0.04820278)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions352352352
Spacing352352352
CellA=B=C: 394.944 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Ternary complex of integrin heterodimer (alpha-v beta-8) and the ...

EntireName: Ternary complex of integrin heterodimer (alpha-v beta-8) and the de novo minibinder protein B8_BP_dslf
Components
  • Complex: Ternary complex of integrin heterodimer (alpha-v beta-8) and the de novo minibinder protein B8_BP_dslf
    • Protein or peptide: Integrin alpha-V heavy chain
    • Protein or peptide: Integrin beta-8
    • Protein or peptide: Minibinder B8_BP_dslf
  • Ligand: CALCIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: MAGNESIUM ION

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Supramolecule #1: Ternary complex of integrin heterodimer (alpha-v beta-8) and the ...

SupramoleculeName: Ternary complex of integrin heterodimer (alpha-v beta-8) and the de novo minibinder protein B8_BP_dslf
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Details: Integrin expressed in expiCHO cells, minibinder expressed in e. coli
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Integrin alpha-V heavy chain

MacromoleculeName: Integrin alpha-V heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 48.31052 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
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 YRARPVITV

UniProtKB: Integrin alpha-V

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Macromolecule #2: Integrin beta-8

MacromoleculeName: Integrin beta-8 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.267992 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: VHVIIPTENE INTQVTPGEV SIQLRPGAEA NFMLKVHPLK KYPVDLYYLV DVSASMHNNI EKLNSVGNDL SRKMAFFSRD FRLGFGSYV DKTVSPYISI HPERIHNQCS DYNLDCMPPH GYIHVLSLTE NITEFEKAVH RQKISGNIDT PEGGFDAMLQ A AVCESHIG ...String:
VHVIIPTENE INTQVTPGEV SIQLRPGAEA NFMLKVHPLK KYPVDLYYLV DVSASMHNNI EKLNSVGNDL SRKMAFFSRD FRLGFGSYV DKTVSPYISI HPERIHNQCS DYNLDCMPPH GYIHVLSLTE NITEFEKAVH RQKISGNIDT PEGGFDAMLQ A AVCESHIG WRKEAKRLLL VMTDQTSHLA LDSKLAGIVC PNDGNCHLKN NVYVKSTTME HPSLGQLSEK LIDNNINVIF AV QGKQFHW YKDLLPLLPG TIAGEIESKA ANLNNLVVEA YQKLISEVKV QVENQVQGIY FNITAICPDG SRKPGMEGCR NVT SNDEVL FNVTVTMKKC DNYAIIKPIG FNETAKIHIH RNC

UniProtKB: Integrin beta-8

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Macromolecule #3: Minibinder B8_BP_dslf

MacromoleculeName: Minibinder B8_BP_dslf / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 8.582782 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
TKCVVRFNFR GDMAVYALKA VKDHLKKEGP HWNITTHNDD EVYLVVRGIH ESDAKRIAKW VESTIPGISV ETQCD

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Macromolecule #6: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 6 / Number of copies: 5 / 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: 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 #8: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 8 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.0 µm

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Image processing

DetailsMovies were collected in super resolution and gain corrected
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 116587
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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