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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA031798-30
Application #
7778340
Study Section
Special Emphasis Panel (NSS)
Program Officer
Knowlton, John R
Project Start
1981-07-01
Project End
2014-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
30
Fiscal Year
2010
Total Cost
$1,004,907
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
059709394
City
Boston
State
MA
Country
United States
Zip Code
02115
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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
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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
Morin, Nicole A; Oakes, Patrick W; Hyun, Young-Min et al. (2008) Nonmuscle myosin heavy chain IIA mediates integrin LFA-1 de-adhesion during T lymphocyte migration. J Exp Med 205:195-205

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