5OPY

Crystal structure of anti-alphaVbeta3 integrin Fab LM609

Summary for 5OPY

• Entry DOI: 10.2210/pdb5opy/pdb
• Descriptor: Heavy chain of LM609 Fab (antigen-binding fragment), Light chain of LM609 Fab (antigen-binding fragment) (3 entities in total)
• Functional Keywords: antigen-binding fragment, fab, lm609, immune system
• Biological source: Mus musculus (House Mouse); More
• Total number of polymer chains: 2
• Total formula weight: 50852.08

Authors

Backovic, M.,Veesler, D.,Borst, A.J.,James, Z.M.,Zagotta, W.,Ginsberg, M.,Rey, F.A.,DiMaio, F. (deposition date: 2017-08-10, release date: 2017-10-25, Last modification date: 2024-11-06)

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

X-RAY DIFFRACTION (2.26 Å)