|Entry||Database: PDB / ID: 6avr|
|Title||Human alpha-V beta-3 Integrin (intermediate conformation) in complex with the therapeutic antibody LM609|
|Keywords||SIGNALING PROTEIN / alpha-V beta-3 integrin / LM609 / vitaxin / abegrin|
|Function / homology||Integrin beta epidermal growth factor like domain 1 / Integrin beta subunit, VWA domain / Cross-presentation of particulate exogenous antigens (phagosomes) / Platelet degranulation / FG-GAP repeat / FG-GAP repeat profile. / EGF-like domain signature 2. / Integrins beta chain cysteine-rich domain signature. / Integrins alpha chain signature. / EGF-like domain signature 1. ...Integrin beta epidermal growth factor like domain 1 / Integrin beta subunit, VWA domain / Cross-presentation of particulate exogenous antigens (phagosomes) / Platelet degranulation / FG-GAP repeat / FG-GAP repeat profile. / EGF-like domain signature 2. / Integrins beta chain cysteine-rich domain signature. / Integrins alpha chain signature. / EGF-like domain signature 1. / Integrin plexin domain / Integrin beta cytoplasmic domain / Integrin alpha / EGF-like domain / Integrin beta tail domain / Integrin alpha chain / Integrin beta subunit, tail / PECAM1 interactions / Integrin beta-3 subunit / Integrin alpha cytoplasmic region / von Willebrand factor A-like domain superfamily / Integrin beta tail domain superfamily / Integrin beta N-terminal / Integrin domain superfamily / Integrin alpha, N-terminal / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / EGF-like domain, extracellular / PSI domain / Integrin beta subunit / Integrin beta subunit, cytoplasmic domain / Integrin alpha-2 / Integrin alpha beta-propellor / FG-GAP repeat / Elastic fibre formation / Integrin beta chain VWA domain / Molecules associated with elastic fibres / Signal transduction by L1 / Integrin alphaIIb beta3 signaling / Integrin cell surface interactions / Syndecan interactions / Laminin interactions / GRB2:SOS provides linkage to MAPK signaling for Integrins / p130Cas linkage to MAPK signaling for integrins / VEGFA-VEGFR2 Pathway / ECM proteoglycans / MAP2K and MAPK activation / Signaling by high-kinase activity BRAF mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling by BRAF and RAF fusions / Signaling by RAS mutants / Neutrophil degranulation / opsonin binding / transforming growth factor-beta secretion / entry of symbiont into host cell by promotion of host phagocytosis / integrin alphav-beta5 complex / integrin alphav-beta8 complex / integrin alphav-beta6 complex / negative regulation of entry of bacterium into host cell / regulation of transforming growth factor beta activation / extracellular matrix protein binding / tube development / alphav-beta3 integrin-vitronectin complex / platelet alpha granule membrane / integrin alphav-beta3 complex / negative regulation of lipoprotein metabolic process / 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 / regulation of postsynaptic neurotransmitter receptor internalization / transforming growth factor beta binding / alphav-beta3 integrin-IGF-1-IGF1R complex / apolipoprotein A-I-mediated signaling pathway / regulation of bone resorption / mesodermal cell differentiation / platelet-derived growth factor receptor binding / regulation of phagocytosis / filopodium membrane / negative regulation of lipid storage / extracellular matrix binding / angiogenesis involved in wound healing / microvillus membrane / heterotypic cell-cell adhesion / protein disulfide isomerase activity / apoptotic cell clearance / cell adhesion mediated by integrin / integrin complex / positive regulation of vascular endothelial growth factor receptor signaling pathway / negative chemotaxis / smooth muscle cell migration / endodermal cell differentiation / cell-substrate adhesion / voltage-gated calcium channel activity / positive regulation of osteoblast proliferation / coreceptor activity / negative regulation of macrophage derived foam cell differentiation / positive regulation of cell adhesion / lamellipodium membrane|
Function and homology information
|Specimen source||Homo sapiens (human)|
Mus musculus (house mouse)
|Method||ELECTRON MICROSCOPY / single particle reconstruction / negative staining / 35 Å resolution|
|Authors||Borst, A.J. / James, Z.N. / Zagotta, W.N. / Ginsberg, M. / Rey, F.A. / DiMaio, F. / Backovic, M. / Veesler, D.|
|Citation||Journal: 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.
SummaryFull reportAbout validation report
|Date||Deposition: Sep 4, 2017 / Release: Nov 1, 2017|
|Structure viewer||Molecule: |
Downloads & links
A: Integrin alpha-V
B: Integrin beta-3
H: Fab LM609 heavy chain
L: Fab LM609 light chain
|#1: Protein/peptide|| |
Mass: 105894.188 Da / Num. of mol.: 1 / Fragment: UNP residues 31-987 / Source: (gene. exp.) Homo sapiens (human) / Gene: ITGAV, MSK8, VNRA, VTNR / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: P06756
|#2: Protein/peptide|| |
Mass: 76523.125 Da / Num. of mol.: 1 / Fragment: UNP residues 27-718 / Source: (gene. exp.) Homo sapiens (human) / Gene: ITGB3, GP3A / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: P05106
|#3: Protein/peptide|| |
Mass: 27223.100 Da / Num. of mol.: 1 / Source: (gene. exp.) Mus musculus (house mouse) / Production host: Drosophila melanogaster (fruit fly)
|#4: Protein/peptide|| |
Mass: 23628.977 Da / Num. of mol.: 1 / Source: (gene. exp.) Mus musculus (house mouse) / Production host: Drosophila melanogaster (fruit fly)
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / Reconstruction method: single particle reconstruction|
|Component||Name: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609|
Type: COMPLEX / Entity ID: 1,
|Molecular weight||Value: 0.23 MDa / Experimental value: NO||Source (natural)||Organism: Homo sapiens (human)||Source (recombinant)||Organism: Drosophila melanogaster (fruit fly)||Buffer solution||pH: 8||Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: YES / Vitrification applied: NO||EM staining||Type: NEGATIVE / Material: Uranyl formate||Specimen support||Grid material: COPPER / Grid mesh size: 400 / Grid type: C-flat 2/0.5|
-Electron microscopy imaging
|Microscopy||Microscope model: FEI TECNAI 12|
|Electron gun||Electron source: LAB6 / Accelerating voltage: 120 / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Electron dose: 30 / Film or detector model: GATAN ULTRASCAN 4000 (4k x 4k)|
|CTF correction||Type: NONE|
|3D reconstruction||Resolution: 35 / Resolution method: FSC 0.5 CUT-OFF / Number of particles: 650 / Symmetry type: POINT|
|Atomic model building||Ref protocol: FLEXIBLE FIT / Ref space: REAL|
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