The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human α V β 3 Integrin via Steric Hindrance
| Autor: | Félix A. Rey, Marija Backovic, David Veesler, Zachary M. James, Mark H. Ginsberg, Andrew J. Borst, Frank DiMaio, William N. Zagotta |
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| Přispěvatelé: | Department of Biochemistry, University of Washington [Seattle], Department of Physiology and Biophysics, Department of Hematology and Oncology, University of California [San Diego] (UC San Diego), University of California-University of California, Virologie Structurale - Structural Virology, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Research reported in this publication was supported by the National Institute of General Medical Sciences under award number 1R01GM120553 (D.V.) and T32GM008268 (A.J.B.), a Pew Scholars award (D.V.), the Raymond and Beverly Sackler Scholars Program in Integrative Biophysics (Z.M.J.), and grant DENtry ANR-05-MIIM-012-02 (F.A.R.). F.A.R. acknowledges support from CNRS and Institut Pasteur recurrent funding, as well as the Pasteur-Weizmann Servier prize, ANR-05-MIIM-0012,DENtry,Entrée des flavivirus dans les cellules cibles : identification et analyse structurale de récepteurs du virus de la Dengue et caractérisation des voies d'entrée virale - Elargissement des études structurales à d'autres virus enveloppés de classe II(2005), University of California (UC)-University of California (UC), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Steric effects abegrin Stereochemistry Angiogenesis medicine.medical_treatment [SDV]Life Sciences [q-bio] Integrin 03 medical and health sciences Structural Biology medicine [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Molecular Biology biology Chemistry alpha V beta 3 integrin 3. Good health 030104 developmental biology Integrin alpha M LM609 antibody Radioimmunotherapy Vitaxin biology.protein Biophysics integrins Integrin beta 6 etaracizumab vitaxin Antibody single-particle electron microscopy medicine.drug |
| Zdroj: | Structure Structure, Elsevier (Cell Press), 2017, 25 (11), pp.1732-1739.e5. ⟨10.1016/j.str.2017.09.007⟩ Structure, 2017, 25 (11), pp.1732-1739.e5. ⟨10.1016/j.str.2017.09.007⟩ |
| ISSN: | 0969-2126 |
| Popis: | International audience; The LM609 antibody specifically recognizes αVβ3 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 αVβ3-targeted radioimmunotherapy. To elucidate the mechanisms of recognition and inhibition of αVβ3 integrin, we solved the structure of the LM609 antigen-binding fragment by X-ray crystallography and determined its binding affinity for αVβ3. Using single-particle electron microscopy, we show that LM609 binds at the interface between the β-propeller domain of the αV chain and the βI domain of the β3 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. |
| Databáze: | OpenAIRE |
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