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- EMDB-7012: Human alpha-V beta-3 Integrin (intermediate conformation) in comp... -

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Entry
Database: EMDB / ID: EMD-7012
TitleHuman alpha-V beta-3 Integrin (intermediate conformation) in complex with the therapeutic antibody LM609
Map dataHuman alpha-V beta-3 Integrin (intermediate conformation) in complex with the therapeutic antibody LM609
Sample
  • Complex: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609
    • Protein or peptide: Integrin alpha-V
    • Protein or peptide: Integrin beta-3
    • Protein or peptide: Fab LM609 heavy chain
    • Protein or peptide: Fab LM609 light chain
Keywordsalpha-V beta-3 integrin / LM609 / vitaxin / abegrin / SIGNALING PROTEIN
Function / homology
Function and homology information


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 / tube development ...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 / tube development / regulation of serotonin uptake / positive regulation of adenylate cyclase-inhibiting opioid receptor signaling pathway / alpha9-beta1 integrin-ADAM8 complex / regulation of trophoblast cell migration / integrin alphaIIb-beta3 complex / regulation of postsynaptic neurotransmitter receptor diffusion trapping / alphav-beta3 integrin-vitronectin complex / regulation of extracellular matrix organization / Laminin interactions / platelet alpha granule membrane / positive regulation of glomerular mesangial cell proliferation / negative regulation of lipoprotein metabolic process / integrin alphav-beta3 complex / fibrinogen binding / entry into host cell by a symbiont-containing vacuole / maintenance of postsynaptic specialization structure / alphav-beta3 integrin-PKCalpha complex / alphav-beta3 integrin-HMGB1 complex / vascular endothelial growth factor receptor 2 binding / blood coagulation, fibrin clot formation / negative regulation of lipid transport / glycinergic synapse / angiogenesis involved in wound healing / regulation of phagocytosis / negative regulation of low-density lipoprotein receptor activity / Elastic fibre formation / regulation of release of sequestered calcium ion into cytosol / mesodermal cell differentiation / alphav-beta3 integrin-IGF-1-IGF1R complex / platelet-derived growth factor receptor binding / cell-substrate junction assembly / transforming growth factor beta binding / positive regulation of small GTPase mediated signal transduction / filopodium membrane / positive regulation of vascular endothelial growth factor receptor signaling pathway / extracellular matrix binding / positive regulation of fibroblast migration / apolipoprotein A-I-mediated signaling pathway / regulation of postsynaptic neurotransmitter receptor internalization / regulation of bone resorption / positive regulation of cell adhesion mediated by integrin / apoptotic cell clearance / wound healing, spreading of epidermal cells / integrin complex / heterotypic cell-cell adhesion / Molecules associated with elastic fibres / positive regulation of intracellular signal transduction / smooth muscle cell migration / positive regulation of cell-matrix adhesion / cell adhesion mediated by integrin / microvillus membrane / negative chemotaxis / Syndecan interactions / cellular response to insulin-like growth factor stimulus / activation of protein kinase activity / p130Cas linkage to MAPK signaling for integrins / protein disulfide isomerase activity / cell-substrate adhesion / positive regulation of smooth muscle cell migration / endodermal cell differentiation / positive regulation of osteoblast proliferation / cellular response to platelet-derived growth factor stimulus / TGF-beta receptor signaling activates SMADs / PECAM1 interactions / GRB2:SOS provides linkage to MAPK signaling for Integrins / lamellipodium membrane / platelet-derived growth factor receptor signaling pathway / negative regulation of macrophage derived foam cell differentiation / fibronectin binding / negative regulation of lipid storage / ECM proteoglycans / positive regulation of bone resorption / positive regulation of T cell migration / vasculogenesis / Integrin cell surface interactions / voltage-gated calcium channel activity / negative regulation of endothelial cell apoptotic process / specific granule membrane / coreceptor activity / phagocytic vesicle / positive regulation of substrate adhesion-dependent cell spreading / extrinsic apoptotic signaling pathway in absence of ligand / cell adhesion molecule binding / positive regulation of endothelial cell proliferation / embryo implantation / ERK1 and ERK2 cascade / positive regulation of endothelial cell migration / Integrin signaling / positive regulation of cell adhesion / substrate adhesion-dependent cell spreading
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 cytoplasmic domain / Integrin_b_cyt / : / Integrin alpha Ig-like domain 3 / Integrin beta tail domain / Integrin beta subunit, tail / Integrin beta tail domain superfamily ...Integrin beta, epidermal growth factor-like domain 1 / Integrin beta epidermal growth factor like domain 1 / Integrin beta subunit, cytoplasmic domain / Integrin beta cytoplasmic domain / Integrin_b_cyt / : / Integrin alpha Ig-like domain 3 / Integrin beta tail domain / Integrin beta subunit, tail / Integrin beta tail domain superfamily / Integrin_B_tail / Integrin beta subunit, VWA domain / Integrin beta subunit / Integrin beta N-terminal / Integrin beta chain VWA domain / Integrin plexin domain / Integrins beta chain cysteine-rich domain signature. / Integrin beta subunits (N-terminal portion of extracellular region) / Integrin alpha cytoplasmic region / EGF-like domain, extracellular / EGF-like domain / 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 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 2. / EGF-like domain signature 1.
Similarity search - Domain/homology
Integrin beta-3 / Integrin alpha-V
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / negative staining / Resolution: 35.0 Å
AuthorsBorst AJ / James ZN
CitationJournal: Structure / Year: 2017
Title: The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human αβ Integrin via Steric Hindrance.
Authors: Andrew J Borst / Zachary M James / William N Zagotta / Mark Ginsberg / Felix A Rey / Frank DiMaio / Marija Backovic / David Veesler /
Abstract: The LM609 antibody specifically recognizes αβ integrin and inhibits angiogenesis, bone resorption, and viral infections in an arginine-glycine-aspartate-independent manner. LM609 entered phase II ...The LM609 antibody specifically recognizes αβ integrin and inhibits angiogenesis, bone resorption, and viral infections in an arginine-glycine-aspartate-independent manner. LM609 entered phase II clinical trials for the treatment of several cancers and was also used for αβ-targeted radioimmunotherapy. To elucidate the mechanisms of recognition and inhibition of αβ integrin, we solved the structure of the LM609 antigen-binding fragment by X-ray crystallography and determined its binding affinity for αβ. Using single-particle electron microscopy, we show that LM609 binds at the interface between the β-propeller domain of the α chain and the βI domain of the β chain, near the RGD-binding site, of all observed integrin conformational states. Integrating these data with fluorescence size-exclusion chromatography, we demonstrate that LM609 sterically hinders access of large ligands to the RGD-binding pocket, without obstructing it. This work provides a structural framework to expedite future efforts utilizing LM609 as a diagnostic or therapeutic tool.
History
DepositionSep 4, 2017-
Header (metadata) releaseNov 1, 2017-
Map releaseNov 1, 2017-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 3.8
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 3.8
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6avr
  • Surface level: 3.8
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_7012.png

Downloads & links

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Map

FileDownload / File: emd_7012.map.gz / Format: CCP4 / Size: 11.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman alpha-V beta-3 Integrin (intermediate conformation) in complex with the therapeutic antibody LM609
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
3.21 Å/pix.
x 144 pix.
= 461.578 Å		3.21 Å/pix.
x 144 pix.
= 461.578 Å		3.21 Å/pix.
x 144 pix.
= 461.578 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 3.2054 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 3.8 / Movie #1: 3.8
Minimum - Maximum-14.180465 - 32.641689999999997
Average (Standard dev.)0.06803627 (±0.9626198)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-72-72-72
Dimensions144144144
Spacing144144144
CellA=B=C: 461.5776 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z3.20540277777783.20540277777783.2054027777778
M x/y/z144144144
origin x/y/z0.0000.0000.000
length x/y/z461.578461.578461.578
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS-72-72-72
NC/NR/NS144144144
D min/max/mean-14.18032.6420.068

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Supplemental data

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Sample components

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Entire : Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609

EntireName: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609
Components
  • Complex: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609
    • Protein or peptide: Integrin alpha-V
    • Protein or peptide: Integrin beta-3
    • Protein or peptide: Fab LM609 heavy chain
    • Protein or peptide: Fab LM609 light chain

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Supramolecule #1: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609

SupramoleculeName: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 230 KDa

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Macromolecule #1: Integrin alpha-V

MacromoleculeName: Integrin alpha-V / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 105.894188 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
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 ARSM PPSFG YSMKGATDID KNGYPDLIVG AFGVDRAILY RARPVITVNA GLEVYPSILN QDNKTCSLPG TALKVSCFNV RFCLK ADGK GVLPRKLNFQ VELLLDKLKQ KGAIRRALFL YSRSPSHSKN MTISRGGLMQ CEELIAYLRD ESEFRDKLTP ITIFME YRL DYRTAADTTG LQPILNQFTP ANISRQAHIL LDCGEDNVCK PKLEVSVDSD QKKIYIGDDN PLTLIVKAQN QGEGAYE AE LIVSIPLQAD FIGVVRNNEA LARLSCAFKT ENQTRQVVCD LGNPMKAGTQ LLAGLRFSVH QQSEMDTSVK FDLQIQSS N LFDKVSPVVS HKVDLAVLAA VEIRGVSSPD HIFLPIPNWE HKENPETEED VGPVVQHIYE LRNNGPSSFS KAMLHLQWP YKYNNNTLLY ILHYDIDGPM NCTSDMEINP LRIKISSLQT TEKNDTVAGQ GERDHLITKR DLALSEGDIH TLGCGVAQCL KIVCQVGRL DRGKSAILYV KSLLWTETFM NKENQNHSYS LKSSASFNVI EFPYKNLPIE DITNSTLVTT NVTWGIQP

UniProtKB: Integrin alpha-V

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Macromolecule #2: Integrin beta-3

MacromoleculeName: Integrin beta-3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 76.523125 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString: GPNICTTRGV SSCQQCLAVS PMCAWCSDEA LPLGSPRCDL KENLLKDNCA PESIEFPVSE ARVLEDRPLS DKGSGDSSQV TQVSPQRIA LRLRPDDSKN FSIQVRQVED YPVDIYYLMD LSYSMKDDLW SIQNLGTKLA TQMRKLTSNL RIGFGAFVDK P VSPYMYIS ...String:
GPNICTTRGV SSCQQCLAVS PMCAWCSDEA LPLGSPRCDL KENLLKDNCA PESIEFPVSE ARVLEDRPLS DKGSGDSSQV TQVSPQRIA LRLRPDDSKN FSIQVRQVED YPVDIYYLMD LSYSMKDDLW SIQNLGTKLA TQMRKLTSNL RIGFGAFVDK P VSPYMYIS PPEALENPCY DMKTTCLPMF GYKHVLTLTD QVTRFNEEVK KQSVSRNRDA PEGGFDAIMQ ATVCDEKIGW RN DASHLLV FTTDAKTHIA LDGRLAGIVQ PNDGQCHVGS DNHYSASTTM DYPSLGLMTE KLSQKNINLI FAVTENVVNL YQN YSELIP GTTVGVLSMD SSNVLQLIVD AYGKIRSKVE LEVRDLPEEL SLSFNATCLN NEVIPGLKSC MGLKIGDTVS FSIE AKVRG CPQEKEKSFT IKPVGFKDSL IVQVTFDCDC ACQAQAEPNS HRCNNGNGTF ECGVCRCGPG WLGSQCECSE EDYRP SQQD ECSPREGQPV CSQRGECLCG QCVCHSSDFG KITGKYCECD DFSCVRYKGE MCSGHGQCSC GDCLCDSDWT GYYCNC TTR TDTCMSSNGL LCSGRGKCEC GSCVCIQPGS YGDTCEKCPT CPDACTFKKE CVECKKFDRG ALHDENTCNR YCRDEIE SV KELKDTGKDA VNCTYKNEDD CVVRFQYYED SSGKSILYVV EEPECPKGPD

UniProtKB: Integrin beta-3

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Macromolecule #3: Fab LM609 heavy chain

MacromoleculeName: Fab LM609 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 27.2231 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString: EVQLEESGGG LVKPGGSLKL SCAASGFAFS SYDMSWVRQI PEKRLEWVAK VSSGGGSTYY LDTVQGRFTI SRDNAKNTLY LQMSSLNSE DTAMYYCARH NYGSFAYWGQ GTLVTVSAAK TTPPSVYPLA PGSAAQTNSM VTLGCLVKGY FPEPVTVTWN S GSLSSGVH ...String:
EVQLEESGGG LVKPGGSLKL SCAASGFAFS SYDMSWVRQI PEKRLEWVAK VSSGGGSTYY LDTVQGRFTI SRDNAKNTLY LQMSSLNSE DTAMYYCARH NYGSFAYWGQ GTLVTVSAAK TTPPSVYPLA PGSAAQTNSM VTLGCLVKGY FPEPVTVTWN S GSLSSGVH TFPAVLQSDL YTLSSSVTVP SSTWPSETVT CNVAHPASST KVDKKIVPRD CGASDDDDKA GWSHPQFEKG GG SGGGSGG GSWSHPQFEK

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Macromolecule #4: Fab LM609 light chain

MacromoleculeName: Fab LM609 light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.628977 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString: ELVMTQTPAT LSVTPGDSVS LSCRASQSIS NHLHWYQQKS HESPRLLIKY ASQSISGIPS RFSGSGSGTD FTLSINSVET EDFGMYFCQ QSNSWPHTFG GGTKLEIKRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS ...String:
ELVMTQTPAT LSVTPGDSVS LSCRASQSIS NHLHWYQQKS HESPRLLIKY ASQSISGIPS RFSGSGSGTD FTLSINSVET EDFGMYFCQ QSNSWPHTFG GGTKLEIKRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS KDSTYSMSST LTLTKDEYER HNSYTCEATH KTSTSPIVKS FNRNEC

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Experimental details

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Structure determination

Methodnegative staining
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
StainingType: NEGATIVE / Material: Uranyl formate
GridModel: C-flat 2/0.5 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Pretreatment - Type: GLOW DISCHARGE

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Electron microscopy

MicroscopeFEI TECNAI 12
Image recordingFilm or detector model: GATAN ULTRASCAN 4000 (4k x 4k) / Average electron dose: 30.0 e/Å2
Electron beamAcceleration voltage: 120 kV / Electron source: LAB6
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD

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Image processing

Startup modelType of model: RANDOM CONICAL TILT
Final reconstructionResolution.type: BY AUTHOR / Resolution: 35.0 Å / Resolution method: FSC 0.5 CUT-OFF / Number images used: 650
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-6avr:
Human alpha-V beta-3 Integrin (intermediate conformation) in complex with the therapeutic antibody LM609

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