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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Knowlton, John R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Immune Disease Institute, Inc.
United States
Zip Code
Sen, Mehmet; Koksal, Adem C; Yuki, Koichi et al. (2018) Ligand- and cation-induced structural alterations of the leukocyte integrin LFA-1. J Biol Chem 293:6565-6577
Moore, Travis I; Aaron, Jesse; Chew, Teng-Leong et al. (2018) Measuring Integrin Conformational Change on the Cell Surface with Super-Resolution Microscopy. Cell Rep 22:1903-1912
Nordenfelt, Pontus; Elliott, Hunter L; Springer, Timothy A (2016) Coordinated integrin activation by actin-dependent force during T-cell migration. Nat Commun 7:13119
Sen, Mehmet; Springer, Timothy A (2016) Leukocyte integrin ?L?2 headpiece structures: The ?I domain, the pocket for the internal ligand, and concerted movements of its loops. Proc Natl Acad Sci U S A 113:2940-5
Springer, Timothy A; Dustin, Michael L (2012) Integrin inside-out signaling and the immunological synapse. Curr Opin Cell Biol 24:107-15
Schurpf, Thomas; Springer, Timothy A (2011) Regulation of integrin affinity on cell surfaces. EMBO J 30:4712-27
Weitz-Schmidt, Gabriele; Schürpf, Thomas; Springer, Timothy A (2011) The C-terminal ?I domain linker as a critical structural element in the conformational activation of ?I integrins. J Biol Chem 286:42115-22
Owens, Róisín M; Gu, Xiaoling; Shin, Miran et al. (2010) Engineering of single Ig superfamily domain of intercellular adhesion molecule 1 (ICAM-1) for native fold and function. J Biol Chem 285:15906-15
Zhang, Hongmin; Liu, Jin-Huan; Yang, Wei et al. (2009) Structural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1. Proc Natl Acad Sci U S A 106:18345-50
Zhang, Hongmin; Casasnovas, Jose M; Jin, Moonsoo et al. (2008) An unusual allosteric mobility of the C-terminal helix of a high-affinity alphaL integrin I domain variant bound to ICAM-5. Mol Cell 31:432-7

Showing the most recent 10 out of 140 publications