5OPY

Crystal structure of anti-alphaVbeta3 integrin Fab LM609

5OPY の概要

• エントリーDOI: 10.2210/pdb5opy/pdb
• 分子名称: Heavy chain of LM609 Fab (antigen-binding fragment), Light chain of LM609 Fab (antigen-binding fragment) (3 entities in total)
• 機能のキーワード: antigen-binding fragment, fab, lm609, immune system
• 由来する生物種: Mus musculus (House Mouse); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 50852.08

構造登録者

Backovic, M.,Veesler, D.,Borst, A.J.,James, Z.M.,Zagotta, W.,Ginsberg, M.,Rey, F.A.,DiMaio, F. (登録日: 2017-08-10, 公開日: 2017-10-25, 最終更新日: 2024-11-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.26 Å)