Therapeutic Antagonists and the Conformational Regulation of the β2 Integrins

The β2 integrins are validated therapeutic targets for inflammatory disorders. Two distinct mechanistic classes of small molecule inhibitors, termed α I allosteric and α / β I-like allosteric antagonist, have recently been developed. The α I allosteric antagonists bind underneath the C-terminal helix of the I domain and stabilize the I domain in the inactive closed conformation. By contrast, the α / β I-like allosteric antagonists bind to the b2 I-like domain MIDAS and disrupt conformational signal transmission between the I and the I-like domain, leaving the I domain in a default inactive form. Furthermore, the two classes of the antagonists have opposite effects on integrin conformation; the a I allosteric antagonists stabilize the bent conformation, whereas the α / β I-like allosteric antagonists induce the extended conformation with inactive I domain. The small molecule antagonists to the β2 integrin highlight the importance of the structural linkages within and between integrin domains for transmission of the conformational signals and regulation of the overall conformation.