Atomic Basis for the Species-specific Inhibition of αV Integrins by Monoclonal Antibody 17E6 Is Revealed by the Crystal Structure of αVβ3 Ectodomain-17E6 Fab Complex

Abstract

Background: 17E6, a primate-specific mouse mAb that inhibits ␣V integrins, is in phase II trials for treating cancer. Results: We determined crystal structure of the ␣V␤3-17E6 Fab complex, revealing the molecular basis of 17E6 specificity and function. Conclusion: 17E6 is an allosteric inhibitor of fibronectin-integrin interaction. Significance: The defined 17E6 epitope may help in developing novel therapeutics targeting related regions in other integrins.

Structural Basis for Simvastatin Competitive Antagonism of Complement Receptor 3

“…First, it is known from RGD-binding integrins, such as the ␤ 3 integrins, that small RGD motif-containing compounds may exert both ligand binding antagonistic and agonistic effects. Binding of these ligand mimetics induces changes in the tertiary structure of the ␤ 3 chain I-like domain (40,41), which persist after dissociation of the compound (42). I domains are structurally highly similar to I-like domains (43).…”

The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human αVβ3 Integrin via Steric Hindrance

“…This argues that LM609 has the potential to interact with α V β 3 receptors prior to inside-out signal activation, which could be leveraged for future therapeutic strategies. Similarly to what has been proposed for the 17E6 antibody (Mahalingam et al, 2014), the full-length LM609 antibody might also interfere with integrin clustering or promote integrin internalization, therefore enhancing therapeutic effects relative to the monovalent Fab LM609.…”

The α-Subunit Regulates Stability of the Metal Ion at the Ligand-associated Metal Ion-binding Site in β3 Integrins

“…The stronger contacts increased fluctuations of the metal ion at LIMBS in ␣ V ␤ 3, as reflected by the ϳ4-fold increase in r.m.s.d., and also increased the mean distances between the coordinating oxygens and the metal ion at LIMBS, as reflected by the reduction in total energy of interaction of the metal ion with the pocket. These observations may offer an explanation for the variable occupancy of LIMBS by metal ion in crystal structures of unliganded ␣ V ␤ 3 ectodomains, where LIMBS was metal-occupied in one (4g1e.pdb, used in this study) (13) but not in four other unliganded ␣ V ␤ 3 ectodomain structures (9,26,29,30). The lack of metal occupancy at LIMBS was attributed to unfavorable crystallization conditions (13).…”