Integrin alpha L I-domain (LFA-1 I-domain)

The Integrin alpha L I-domain, also known as the LFA-1 I-domain, is a specialized structural region within the alpha L subunit (CD11a) of the Lymphocyte Function-associated Antigen-1 (LFA-1) integrin complex [1.3.1, 1.5.1]. It is primarily responsible for mediating the high-affinity interaction between leukocytes and their ligands, such as Intercellular Adhesion Molecule-1 (ICAM-1) [1.1.3, 1.5.2]. The domain contains a Metal Ion-Dependent Adhesion Site (MIDAS) that requires divalent cations like magnesium to coordinate ligand binding [1.1.1, 1.5.1]. Conformational shifts in the I-domain, transitioning from a closed low-affinity state to an open high-affinity state, are essential for firm leukocyte adhesion and transmigration across the endothelium [1.1.2, 1.1.5]. This target plays a pivotal role in the immune response, including T-cell activation and the formation of the immunological synapse [1.3.2, 1.5.3]. Dysregulation of LFA-1 activity is associated with various inflammatory and autoimmune diseases, as well as certain leukemias and metastatic processes [1.2.4, 1.3.3]. Pharmacological targeting of the I-domain involves both competitive antagonists that block the MIDAS and allosteric inhibitors that stabilize the inactive conformation [1.1.2, 1.1.3]. Notable drugs targeting this domain include Lifitegrast, used for dry eye disease, and Efalizumab, which was previously used for psoriasis but withdrawn due to safety concerns [1.2.5, 1.3.1].

Other names

CD11a I-domainITGAL I-domainLymphocyte function-associated antigen 1 alpha subunit I-domainInserted domain of integrin alpha LIntegrin alpha-L I-domain

Antagonism of the interaction between LFA-1 and its ligand ICAM-1 by binding to the I-domain, either competitively at the metal ion-dependent adhesion site (MIDAS) or allosterically at the I-domain allosteric site (IDAS) to stabilize the low-affinity (closed) conformation [1.1.1, 1.1.2, 1.1.3].