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Identification and X-ray co-crystal structure of a small-molecule activator of LFA-1-ICAM-1 binding

Hintersteiner, Martin, Kallen, Joerg, Gstach, Hubert and Auer, Manfred (2014) Identification and X-ray co-crystal structure of a small-molecule activator of LFA-1-ICAM-1 binding. to be determined, 53 (17). pp. 4322-4326. ISSN 14337851


The integrin Leucocyte function associated antigen 1 (LFA-1) is a heterodimeric immune receptor ubiquitously expressed on all leucocytes. Its interaction with Intercellular adhesion molecule 1 (ICAM-1) provides a critical recognition event between T-cells and antigen presenting cells in the immune systems efforts to pull off an early stage cell mediated immune response.[1–3] The LFA-1/ICAM-1 axis has thus been explored as a target interaction for drug discovery.[4–7] Furthermore, the structural changes of LFA-1 upon activation and interaction with ICAM-1 also make the LFA-1/ICAM-1 interaction an interesting example of protein-protein interaction (PPI) inhibition by small molecule inhibitors.[8,9]
While protein-protein interaction inhibition by small molecules is considered to be the ultimate art in drug design, even fewer examples of true agonists of PPIs have been reported.[10–12] As for LFA-1, such activators would have interesting applications in rare hereditary genetic disorders called Leucocyte adhesion deficiency (LAD) or as potential enhancers of tumour immunotherapy.[13,14] Although, one such activator has been described recently, closer biological investigation has shown that it ultimately worked as an inhibitor on a cellular level by locking the LFA-1/ICAM-1 interaction when reversibility was needed for detachment of immune cells from endothelial surfaces and tissue infiltration.[15]
Herein we describe the identification and structural biology of IBE-667, an ICAM-1 binding enhancer for LFA-1 from on-bead screening of tagged one-bead one-compound combinatorial libraries by confocal nanoscanning and bead picking (CONA).[16] Cellular assays demonstrate the activity of IBE-667 in promoting the binding of LFA-1 on activated immune cells to ICAM-1. X-ray structure based analysis did not only allow us to explain the molecular features of IBE-667 binding to LFA-1 but also offers an explanation for its mode of action.

Item Type: Article
Keywords: LFA-1, ICAM-1, protein-protein interaction, integrin, AIDA dye
Date Deposited: 02 May 2016 23:45
Last Modified: 04 Jul 2016 23:46


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