Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 49, Pages 37904-37912Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M606888200
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Funding
- NCI NIH HHS [CA31798, R37 CA031798, R01 CA031798] Funding Source: Medline
- NIAID NIH HHS [AI63421, R01 AI063421] Funding Source: Medline
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The binding of integrin alpha(L)beta(2) to its ligand intercellular adhesion molecule-1 is required for immune responses and leukocyte trafficking. Small molecule antagonists of alpha(L)beta(2) are under intense investigation as potential anti-inflammatory drugs. We describe for the first time a small molecule integrin agonist. A previously described alpha/beta I allosteric inhibitor, compound 4, functions as an agonist of alpha(L)beta(2) in Ca2+ and Mg2+ and as an antagonist in Mn2+. We have characterized the mechanism of activation and its competitive and noncompetitive inhibition by different compounds. Although it stimulates ligand binding, compound 4 nonetheless inhibits lymphocyte transendothelial migration. Agonism by compound 4 results in accumulation of alpha(L)beta(2) in the uropod, extreme uropod elongation, and defective de-adhesion. Small molecule integrin agonists open up novel therapeutic possibilities.
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