Integrin alpha-L (ITGAL) (ITGAL)

Integrin alpha-L (ITGAL), also known as CD11a, is a transmembrane protein that combines with the beta-2 subunit (CD18) to form the heterodimeric integrin Lymphocyte Function-associated Antigen-1 (LFA-1) [UniProt P20023]. It is expressed on the surface of all leukocytes and is vital for immune cell adhesion, migration, and signaling [PubMed: 12910223]. The primary ligand for LFA-1 is Intercellular Adhesion Molecule-1 (ICAM-1), and their interaction is crucial for leukocyte recruitment to sites of inflammation and the formation of the immunological synapse [PubMed: 27543165]. The allosteric site on the alpha-L I-domain serves as a regulatory region where small molecule antagonists can bind to stabilize the integrin in an inactive, low-affinity state [Nature Reviews Drug Discovery, 2003]. This inhibition prevents the binding of ICAM-1, thereby dampening T-cell mediated inflammatory responses [PubChem: Lifitegrast]. Therapeutically, targeting this allosteric site has proven effective in treating conditions like dry eye disease, where lifitegrast is used to block the LFA-1/ICAM-1 interaction on the ocular surface [FDA: Xiidra Label]. However, systemic inhibition of this pathway has historically been associated with risks such as progressive multifocal leukoencephalopathy, leading to the withdrawal of earlier biologics like efalizumab [FDA: Efalizumab Safety].

Other names

CD11aLFA-1 alpha subunitLymphocyte function-associated antigen 1 alpha subunitAntigen CD11AIntegrin alpha-L allosteric siteITGAL

Small molecule antagonists bind to the I-domain allosteric site (IDAS) of the Integrin alpha-L subunit, inducing a conformational change that stabilizes the protein in a low-affinity state, thereby preventing its interaction with ICAM-1 [Nature Reviews Drug Discovery, 2003; PubChem: Lifitegrast].