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- PDB-6avq: The Therapeutic Antibody LM609 Selectively Inhibits Ligand Bindin... -

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Basic information

Entry
Database: PDB / ID: 6avq
TitleThe Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human alpha-V beta-3 Integrin via Steric Hindrance
Components
  • Integrin alpha-VIntegrin alpha V
  • Integrin beta-3Integrin beta 3
  • LM609 Fab heavy chain
  • LM609 Fab light chain
KeywordsSIGNALING PROTEIN / alpha-V beta-3 integrin / LM609 / vitaxin / abegrin
Function / homologyFG-GAP repeat profile. / Integrin beta subunit / ECM proteoglycans / Syndecan interactions / von Willebrand factor A-like domain superfamily / Integrin beta tail domain superfamily / Laminin interactions / Integrin beta N-terminal / Integrin domain superfamily / Integrin beta-3 subunit ...FG-GAP repeat profile. / Integrin beta subunit / ECM proteoglycans / Syndecan interactions / von Willebrand factor A-like domain superfamily / Integrin beta tail domain superfamily / Laminin interactions / Integrin beta N-terminal / Integrin domain superfamily / Integrin beta-3 subunit / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / PSI domain / Platelet degranulation / Integrin cell surface interactions / Integrin beta chain VWA domain / Integrin beta subunit, cytoplasmic domain / Molecules associated with elastic fibres / Integrin alpha-2 / Integrin alpha beta-propellor / FG-GAP repeat / PECAM1 interactions / Elastic fibre formation / EGF-like domain, extracellular / Integrin beta subunit, tail / Integrin beta subunit, VWA domain / Integrin alpha chain / Cross-presentation of particulate exogenous antigens (phagosomes) / Integrin alpha cytoplasmic region / Integrin alpha, N-terminal / Integrin alphaIIb beta3 signaling / Integrins alpha chain signature. / Signaling by moderate kinase activity BRAF mutants / MAP2K and MAPK activation / Signaling by high-kinase activity BRAF mutants / Signaling by RAS mutants / Integrin alpha / Integrin beta cytoplasmic domain / Integrin plexin domain / Signal transduction by L1 / EGF-like domain signature 1. / GRB2:SOS provides linkage to MAPK signaling for Integrins / Signaling by BRAF and RAF fusions / EGF-like domain / Integrins beta chain cysteine-rich domain signature. / Paradoxical activation of RAF signaling by kinase inactive BRAF / Integrin beta tail domain / FG-GAP repeat / VEGFA-VEGFR2 Pathway / p130Cas linkage to MAPK signaling for integrins / EGF-like domain signature 2. / 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 / regulation of phagocytosis / filopodium membrane / platelet-derived growth factor receptor binding / cell adhesion mediated by integrin / negative regulation of lipid storage / extracellular matrix binding / heterotypic cell-cell adhesion / angiogenesis involved in wound healing / apoptotic cell clearance / microvillus membrane / 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 / endodermal cell differentiation / voltage-gated calcium channel activity / 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 / fibronectin binding / vasculogenesis
Function and homology information
Specimen sourceHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / negative staining / 35 Å resolution
AuthorsBorst, A.J. / James, Z.N. / Zagotta, W.N. / Ginsberg, M. / Rey, F.A. / DiMaio, F. / Backovic, M. / Veesler, D.
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 Report
SummaryFull reportAbout validation report
DateDeposition: Sep 4, 2017 / Release: Nov 1, 2017
RevisionDateData content typeGroupCategoryItemProviderType
1.0Nov 1, 2017Structure modelrepositoryInitial release
1.1Nov 15, 2017Structure modelDatabase referencescitation_citation.journal_volume / _citation.page_first / _citation.page_last
1.2Jul 18, 2018Structure modelData collectionem_software_em_software.name

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Assembly

Deposited unit
A: Integrin alpha-V
B: Integrin beta-3
H: LM609 Fab heavy chain
L: LM609 Fab light chain


Theoretical massNumber of molelcules
Total (without water)233,2694
Polyers233,2694
Non-polymers00
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein/peptide Integrin alpha-V / Integrin alpha V / Vitronectin receptor / Vitronectin receptor subunit alpha


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 Integrin beta-3 / Integrin beta 3 / Platelet membrane glycoprotein IIIa / GPIIIa


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 LM609 Fab heavy chain


Mass: 27223.100 Da / Num. of mol.: 1 / Source: (gene. exp.) Mus musculus (house mouse) / Production host: Drosophila melanogaster (fruit fly)
#4: Protein/peptide LM609 Fab light chain


Mass: 23628.977 Da / Num. of mol.: 1 / Source: (gene. exp.) Mus musculus (house mouse) / Production host: Drosophila melanogaster (fruit fly)

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / Reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Quaternary complex of human alpha-V beta-3 integrin with the Fab LM609
Type: COMPLEX / Entity ID: 1, 2, 3, 4 / Source: RECOMBINANT
Molecular weightValue: 0.23 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Drosophila melanogaster (fruit fly)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: YES / Vitrification applied: NO
EM stainingType: NEGATIVE / Material: Uranyl formate
Specimen supportGrid material: COPPER / Grid mesh size: 400 / Grid type: C-flat 2/0.5

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Electron microscopy imaging

MicroscopyMicroscope model: FEI TECNAI 12
Electron gunElectron source: LAB6 / Accelerating voltage: 120 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 30 e/Å2 / Film or detector model: GATAN ULTRASCAN 4000 (4k x 4k)

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Processing

EM software
IDNameCategory
7UCSF Chimeramodel fitting
13Rosettamodel refinement
CTF correctionType: NONE
SymmetryPoint symmetry: C1
3D reconstructionResolution: 35 Å / Resolution method: FSC 0.5 CUT-OFF / Number of particles: 650 / Symmetry type: POINT
Atomic model buildingRef protocol: FLEXIBLE FIT / Ref space: REAL

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