Small molecule integrin antagonists that bind to the beta2 subunit I-like domain and activate signals in one direction and block them in the other.
Leukocyte integrins contain an inserted (I) domain in their alpha subunits and an I-like domain in their beta(2) subunit, which directly bind ligand and regulate ligand binding, respectively. We describe a novel mechanistic class of integrin inhibitors that bind to the metal ion-dependent adhesion site of the beta(2) I-like domain and prevent its interaction with and activation of the alpha(L) I domain. The inhibitors do not bind to the alpha(L) I domain but stabilize alpha/beta subunit association and can show selectivity for alpha(L)beta(2) compared to alpha(M)beta(2). The inhibitors reveal a crucial intersection for relaying conformational signals within integrin extracellular domains. While blocking signals in one direction to the I domain, the antagonists induce the active conformation of the I-like domain and stalk domains, and thus transmit conformational signals in the other direction toward the transmembrane domains.
D000494:Allosteric Regulation / Q000502:physiology; D000495:Allosteric Site / Q000502:physiology; D000818:Animals; D016023:Integrins / Q000037:antagonists & inhibitors*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D051379:Mice; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*
D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen