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 Cited by 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: 29033288DOI: 10.1016/j.str.2017.09.007 PDB entries with the same primary citation |
Experimental method | ELECTRON MICROSCOPY (35 Å) |
Structure validation
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