Lymphocyte function-associated antigen 1 (LFA-1, or integrin aifa) and its ligands, the five different intercellular adhesion molecules (ICAMs), are important in antigen-specific immune responses, homing and trafficking of leukocytes between vascular and extravascular spaces, and in tumor surveillance. The antibody Efalizumab (Raptiva) to the I domain in the LFA-1 a subunit is in clinical use for treatment of psoriasis. Two classes of small molecule inhibitors that we call, according to their mode of action, a I allostericantagonists and o/p I allosteric antagonists, are in clinical trials andpre-clinical development, respectively. Inthe next grant period, we will extend understanding of the structure and function of LFA-1 and ICAMs withfour specific aims. 1) We will determine the structure of chimeras with the LFA-1 headpiece in a bent, low-affinity conformation with andwithout bound a I ando/p I allosteric antagonists. 2) Wewill determine the structureof an LFA-1 headpiece fragment, which contains the ligand binding domains but not the flexible lower leg domains. 3) We will extend structural studies on ICAM-1. 4) We will use the 125l-labeled high affinity ICAM-1 mutant to measure the monomeric affinity of cell surface LFA-1. The integrin LFA-1 is an important drug target in autoimmune disease, with one approved antibody antagonist and multiple small molecule antagonists in development. The molecular characterizationof LFA-1 and its antagonists proposed in this grant will enhance development of new drugs.
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