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TitleThe Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human αβ Integrin via Steric Hindrance.
Journal, issue, pagesStructure, Vol. 25, Issue 11, Page 1732-11739.e5, Year 2017
Publish dateNov 7, 2017
AuthorsAndrew J Borst / Zachary M James / William N Zagotta / Mark Ginsberg / Felix A Rey / Frank DiMaio / Marija Backovic / David Veesler /
PubMed AbstractThe 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.
External linksStructure / PubMed:29033288 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.26 - 35.0 Å
Structure data

EMDB-7011, PDB-6avq:
The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human alpha-V beta-3 Integrin via Steric Hindrance
Method: EM (single particle) / Resolution: 35.0 Å

EMDB-7012, PDB-6avr:
Human alpha-V beta-3 Integrin (intermediate conformation) in complex with the therapeutic antibody LM609
Method: EM (single particle) / Resolution: 35.0 Å

EMDB-7013, PDB-6avu:
Human alpha-V beta-3 Integrin (open conformation) in complex with the therapeutic antibody LM609
Method: EM (single particle) / Resolution: 35.0 Å

PDB-5opy:
Crystal structure of anti-alphaVbeta3 integrin Fab LM609
Method: X-RAY DIFFRACTION / Resolution: 2.26 Å

Chemicals

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsIMMUNE SYSTEM / Antigen-binding fragment / Fab / LM609 / SIGNALING PROTEIN / alpha-V beta-3 integrin / vitaxin / abegrin

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