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- EMDB-7011: The Therapeutic Antibody LM609 Selectively Inhibits Ligand Bindin... -

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Entry
Database: EMDB / ID: EMD-7011
TitleThe Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human alpha-V beta-3 Integrin via Steric Hindrance
Map dataThe Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human alpha-V beta-3 Integrin via Steric Hindrance
Sample
  • Complex: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609
    • Protein or peptide: Integrin alpha-VIntegrin alpha V
    • Protein or peptide: Integrin beta-3Integrin beta 3
    • Protein or peptide: LM609 Fab heavy chain
    • Protein or peptide: LM609 Fab light chain
Keywordsalpha-V beta-3 integrin / LM609 / vitaxin / abegrin / SIGNALING PROTEIN
Function / homology
Function and homology information


integrin alphav-beta6 complex / integrin alphav-beta8 complex / transforming growth factor beta production / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / : / opsonin binding / Cross-presentation of particulate exogenous antigens (phagosomes) / extracellular matrix protein binding / tube development ...integrin alphav-beta6 complex / integrin alphav-beta8 complex / transforming growth factor beta production / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / : / opsonin binding / 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 / regulation of postsynaptic neurotransmitter receptor diffusion trapping / alphav-beta3 integrin-vitronectin complex / maintenance of postsynaptic specialization structure / Laminin interactions / positive regulation of glomerular mesangial cell proliferation / regulation of extracellular matrix organization / platelet alpha granule membrane / integrin alphav-beta3 complex / negative regulation of lipoprotein metabolic process / entry into host cell by a symbiont-containing vacuole / alphav-beta3 integrin-PKCalpha complex / fibrinogen binding / glycinergic synapse / alphav-beta3 integrin-HMGB1 complex / vascular endothelial growth factor receptor 2 binding / blood coagulation, fibrin clot formation / negative regulation of lipid transport / negative regulation of low-density lipoprotein receptor activity / regulation of phagocytosis / Elastic fibre formation / cell-substrate junction assembly / regulation of release of sequestered calcium ion into cytosol / mesodermal cell differentiation / transforming growth factor beta binding / alphav-beta3 integrin-IGF-1-IGF1R complex / angiogenesis involved in wound healing / platelet-derived growth factor receptor binding / filopodium membrane / positive regulation of small GTPase mediated signal transduction / extracellular matrix binding / positive regulation of fibroblast migration / positive regulation of vascular endothelial growth factor receptor signaling pathway / regulation of postsynaptic neurotransmitter receptor internalization / apolipoprotein A-I-mediated signaling pathway / regulation of bone resorption / apoptotic cell clearance / heterotypic cell-cell adhesion / integrin complex / positive regulation of cell adhesion mediated by integrin / positive regulation of intracellular signal transduction / Molecules associated with elastic fibres / cellular response to insulin-like growth factor stimulus / positive regulation of cell-matrix adhesion / cell adhesion mediated by integrin / smooth muscle cell migration / microvillus membrane / Syndecan interactions / negative chemotaxis / endodermal cell differentiation / p130Cas linkage to MAPK signaling for integrins / cellular response to platelet-derived growth factor stimulus / protein disulfide isomerase activity / cell-substrate adhesion / positive regulation of smooth muscle cell migration / activation of protein kinase activity / TGF-beta receptor signaling activates SMADs / positive regulation of osteoblast proliferation / PECAM1 interactions / lamellipodium membrane / GRB2:SOS provides linkage to MAPK signaling for Integrins / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / platelet-derived growth factor receptor signaling pathway / fibronectin binding / positive regulation of cell adhesion / ECM proteoglycans / voltage-gated calcium channel activity / positive regulation of T cell migration / positive regulation of bone resorption / vasculogenesis / Integrin cell surface interactions / specific granule membrane / coreceptor activity / phagocytic vesicle / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / embryo implantation / extrinsic apoptotic signaling pathway in absence of ligand / ERK1 and ERK2 cascade / positive regulation of endothelial cell proliferation / cell adhesion molecule binding / cell-matrix adhesion / Integrin signaling / substrate adhesion-dependent cell spreading / response to activity / positive regulation of endothelial cell migration
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 Ig-like domain 2 / Integrin alpha chain / Integrin alpha beta-propellor / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / 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 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
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R01GM120553 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32GM008268 United States
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: 3.5
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 3.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6avq
  • Surface level: 3.5
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_7011.map.gz / Format: CCP4 / Size: 11.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThe Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human alpha-V beta-3 Integrin via Steric Hindrance
Voxel sizeX=Y=Z: 3.2054 Å
Density
Contour LevelBy AUTHOR: 3.5 / Movie #1: 3.5
Minimum - Maximum-15.005414999999999 - 30.678084999999999
Average (Standard dev.)0.02069299 (±0.9798952)
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-15.00530.6780.021

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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-VIntegrin alpha V
    • Protein or peptide: Integrin beta-3Integrin beta 3
    • Protein or peptide: LM609 Fab heavy chain
    • Protein or peptide: LM609 Fab 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: LM609 Fab heavy chain

MacromoleculeName: LM609 Fab 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: LM609 Fab light chain

MacromoleculeName: LM609 Fab 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
Electron beamAcceleration voltage: 120 kV / Electron source: LAB6
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN ULTRASCAN 4000 (4k x 4k) / Average electron dose: 30.0 e/Å2

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Image processing

Startup modelType of model: RANDOM CONICAL TILT
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 35.0 Å / Resolution method: FSC 0.5 CUT-OFF / Number images used: 650

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-6avq:
The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human alpha-V beta-3 Integrin via Steric Hindrance

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