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

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Entry
Database: EMDB / ID: 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
SampleQuaternary complex of human alpha-V beta-3 integrin with the Fab LM609:
Integrin alpha-VIntegrin alpha V / Integrin beta-3Integrin beta 3 / LM609 Fab heavy chain / LM609 Fab light chain
Function / homologyPlatelet degranulation / PSI domain / ECM proteoglycans / Syndecan interactions / Integrin alpha cytoplasmic region / von Willebrand factor A-like domain superfamily / Laminin interactions / Integrin beta tail domain superfamily / Integrin beta N-terminal / Integrin alpha, N-terminal ...Platelet degranulation / PSI domain / ECM proteoglycans / Syndecan interactions / Integrin alpha cytoplasmic region / von Willebrand factor A-like domain superfamily / Laminin interactions / Integrin beta tail domain superfamily / Integrin beta N-terminal / Integrin alpha, N-terminal / Integrin beta-3 subunit / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / Cross-presentation of particulate exogenous antigens (phagosomes) / Integrin cell surface interactions / FG-GAP repeat / Integrin beta subunit / Molecules associated with elastic fibres / Integrin beta subunit, cytoplasmic domain / Integrin alpha-2 / Integrin alpha beta-propellor / FG-GAP repeat / PECAM1 interactions / EGF-like domain, extracellular / Integrin beta subunit, tail / Integrin beta subunit, VWA domain / Integrin alpha chain / Elastic fibre formation / Integrin beta chain VWA domain / Integrin domain superfamily / Integrin alphaIIb beta3 signaling / Integrins beta chain cysteine-rich domain signature. / Signaling by moderate kinase activity BRAF mutants / MAP2K and MAPK activation / Signaling by high-kinase activity BRAF mutants / Signaling by RAS mutants / Integrin beta cytoplasmic domain / Integrin plexin domain / EGF-like domain signature 1. / Signal transduction by L1 / Integrins alpha chain signature. / GRB2:SOS provides linkage to MAPK signaling for Integrins / Signaling by BRAF and RAF fusions / Integrin alpha / EGF-like domain signature 2. / Paradoxical activation of RAF signaling by kinase inactive BRAF / EGF-like domain / Integrin beta tail domain / VEGFA-VEGFR2 Pathway / p130Cas linkage to MAPK signaling for integrins / FG-GAP repeat profile. / Neutrophil degranulation / opsonin binding / entry of symbiont into host cell by promotion of host phagocytosis / integrin alphav-beta5 complex / integrin alphav-beta6 complex / integrin alphav-beta8 complex / transforming growth factor-beta secretion / negative regulation of entry of bacterium into host cell / extracellular matrix protein binding / tube development / alphav-beta3 integrin-vitronectin complex / platelet alpha granule membrane / negative regulation of lipoprotein metabolic process / integrin alphav-beta3 complex / negative regulation of low-density lipoprotein particle receptor biosynthetic process / alphav-beta3 integrin-PKCalpha complex / alphav-beta3 integrin-HMGB1 complex / vascular endothelial growth factor receptor 2 binding / negative regulation of lipid transport / transforming growth factor beta binding / alphav-beta3 integrin-IGF-1-IGF1R complex / apolipoprotein A-I-mediated signaling pathway / mesodermal cell differentiation / regulation of bone resorption / filopodium membrane / platelet-derived growth factor receptor binding / regulation of phagocytosis / cell adhesion mediated by integrin / negative regulation of lipid storage / extracellular matrix binding / angiogenesis involved in wound healing / microvillus membrane / heterotypic cell-cell adhesion / apoptotic cell clearance / negative chemotaxis / integrin complex / protein disulfide isomerase activity / positive regulation of vascular endothelial growth factor receptor signaling pathway / smooth muscle cell migration / cell-substrate adhesion / voltage-gated calcium channel activity / endodermal cell differentiation / coreceptor activity / positive regulation of osteoblast proliferation / positive regulation of cell adhesion / negative regulation of macrophage derived foam cell differentiation / lamellipodium membrane / specific granule membrane / calcium ion transmembrane transport / vasculogenesis
Function and homology information
SourceHomo sapiens (human)
Methodsingle particle reconstruction / 35 Å resolution
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.
Validation ReportPDB-ID: 6avq

SummaryFull reportAbout validation report
DateDeposition: Sep 4, 2017 / Header (metadata) release: Nov 1, 2017 / Map release: Nov 1, 2017 / Last update: Nov 15, 2017

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 3.5
  • Imaged by UCSF Chimera
  • Download
  • 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
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

Fileemd_7011.map.gz (map file in CCP4 format, 11944 KB)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
144 pix
3.21 Å/pix.
= 461.578 Å
144 pix
3.21 Å/pix.
= 461.578 Å
144 pix
3.21 Å/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
Contour Level:3.5 (by author), 3.5 (movie #1):
Minimum - Maximum-15.005415 - 30.678085
Average (Standard dev.)0.02069299 (0.9798952)
Details

EMDB XML:

Space Group Number1
Map Geometry
Axis orderXYZ
Dimensions144144144
Origin-72-72-72
Limit717171
Spacing144144144
CellA=B=C: 461.5776 Å
α=β=γ: 90 deg.

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
start NX/NY/NZ
NX/NY/NZ
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
Number of components: 5
MassTheoretical: 230 kDa

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Component #1: protein, Quaternary complex of human alpha-V beta-3 integrin with...

ProteinName: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609
Recombinant expression: No
MassTheoretical: 230 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Drosophila melanogaster (fruit fly)

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Component #2: protein, Integrin alpha-V

ProteinName: Integrin alpha-VIntegrin alpha V / Recombinant expression: No
MassTheoretical: 105.894188 kDa
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: protein, Integrin beta-3

ProteinName: Integrin beta-3Integrin beta 3 / Recombinant expression: No
MassTheoretical: 76.523125 kDa
Source (engineered)Expression System: Homo sapiens (human)

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Component #4: protein, LM609 Fab heavy chain

ProteinName: LM609 Fab heavy chain / Recombinant expression: No
MassTheoretical: 27.2231 kDa
Source (engineered)Expression System: Mus musculus (house mouse)

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Component #5: protein, LM609 Fab light chain

ProteinName: LM609 Fab light chain / Recombinant expression: No
MassTheoretical: 23.628977 kDa
Source (engineered)Expression System: Mus musculus (house mouse)

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Experimental details

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Sample preparation

SpecimenSpecimen state: particle
Sample solutionpH: 8
VitrificationCryogen name: NONE

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Electron microscopy imaging

ImagingMicroscope: FEI TECNAI 12
Electron gunElectron source: LAB6 / Accelerating voltage: 120 kV / Electron dose: 30 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN ULTRASCAN 4000 (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 650
3D reconstructionResolution: 35 Å / Resolution method: FSC 0.5 CUT-OFF

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Atomic model buiding

Output model

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