6AVU

Human alpha-V beta-3 Integrin (open conformation) in complex with the therapeutic antibody LM609

Summary for 6AVU

• Entry DOI: 10.2210/pdb6avu/pdb
• Related: 5OPY 6AVQ 6AVR
• EMDB information: 7011 7012 7013
• Descriptor: Integrin alpha-V, Integrin beta-3, Fab LM609 heavy chain, ... (4 entities in total)
• Functional Keywords: alpha-v beta-3 integrin, lm609, vitaxin, abegrin, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 233269.39

Authors

Borst, A.J.,James, Z.N.,Zagotta, W.N.,Ginsberg, M.,Rey, F.A.,DiMaio, F.,Backovic, M.,Veesler, D. (deposition date: 2017-09-04, release date: 2017-11-01, Last modification date: 2024-03-13)

Primary citation

Borst, A.J.,James, Z.M.,Zagotta, W.N.,Ginsberg, M.,Rey, F.A.,DiMaio, F.,Backovic, M.,Veesler, D.
The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human alpha V beta 3 Integrin via Steric Hindrance.
Structure, 25:1732-1739.e5, 2017

PubMed 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 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.

PubMed: 29033288
DOI: 10.1016/j.str.2017.09.007

Experimental method

ELECTRON MICROSCOPY (35 Å)