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Competition Between Intercellular Adhesion molecule-1 and a Small-Molecule Antagonist for a Common Binding Site on the Alphal Subunit of Lymphocyte Function-Associated antigen-1

Competition Between Intercellular Adhesion molecule-1 and a Small-Molecule Antagonist for a Common Binding Site on the Alphal Subunit of Lymphocyte Function-Associated antigen-1

Susan M Keating, Kevin R Clark, Lisa D Stefanich, Fred Arellano, Caroline P Edwards, Sarah C Bodary, Steven A Spencer, Thomas R Gadek, James C Marsters Jr, Maureen H Beresini

Protein Sci. 2006 Feb;15(2):290-303.

PMID: 16384997

Abstract:

The lymphocyte function-associated antigen-1 (LFA-1) binding of a unique class of small-molecule antagonists as represented by compound 3 was analyzed in comparison to that of soluble intercellular adhesion molecule-1 (sICAM-1) and A-286982, which respectively define direct and allosteric competitive binding sites within LFA-1's inserted (I) domain. All three molecules antagonized LFA-1 binding to ICAM-1-Immunoglobulin G fusion (ICAM-1-Ig) in a competition ELISA, but only compound 3 and sICAM-1 inhibited the binding of a fluorescein-labeled analog of compound 3 to LFA-1. Compound 3 and sICAM-1 displayed classical direct competitive binding behavior with ICAM-1. Their antagonism of LFA-1 was surmountable by both ICAM-1-Ig and a fluorescein-labeled compound 3 analog. The competition of both sICAM-1 and compound 3 with ICAM-1-Ig for LFA-1 resulted in equivalent and linear Schild plots with slopes of 1.24 and 1.26, respectively. Cross-linking studies with a photoactivated analog of compound 3 localized the high-affinity small-molecule binding site to the N-terminal 507 amino acid segment of the alpha chain of LFA-1, a region that includes the I domain. In addition, cells transfected with a variant of LFA-1 lacking this I domain showed no significant binding of a fluorescein-labeled analog of compound 3 or ICAM-1-Ig. These results demonstrate that compound 3 inhibits the LFA-1/ICAM-1 binding interaction in a directly competitive manner by binding to a high-affinity site on LFA-1. This binding site overlaps with the ICAM-1 binding site on the alpha subunit of LFA-1, which has previously been localized to the I domain.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP280749179	A-286982		280749-17-9	Price

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