期刊
STRUCTURE
卷 25, 期 11, 页码 1732-+出版社
CELL PRESS
DOI: 10.1016/j.str.2017.09.007
关键词
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资金
- National Institute of General Medical Sciences [1R01GM120553, T32GM008268]
- Raymond and Beverly Sackler Scholars Program in Integrative Biophysics
- DENtry [ANR-05-MIIM-012-02]
- CNRS
- Institut Pasteur
The LM609 antibody specifically recognizes alpha(V)beta(3) integrin and inhibits angiogenesis, bone resorption, and viral infections in an arginine-glycine-aspartatein-dependent manner. LM609 entered phase II clinical trials for the treatment of several cancers and was also used for alpha(V)beta(3)-targeted radioimmunotherapy. To elucidate the mechanisms of recognition and inhibition of alpha(V)beta(3) integrin, we solved the structure of the LM609 antigen-binding fragment by X-ray crystallography and determined its binding affinity for alpha(V)beta(3). Using single-particle electron microscopy, we show that LM609 binds at the interface between the beta-propeller domain of the alpha(V) chain and the beta I domain of the beta(3) 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.
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