A small-molecule inhibitor of lectin-like oxidized LDL receptor-1 acts by stabilizing an inactive receptor tetramer state
Autor: | Dennis Fiegen, Ralf Heilker, Herbert Nar, Iain Lingard, Klaus Klinder, Michael Wolff, Heike Neubauer, Jürgen Prestle, Francois Debaene, Gisela Schnapp, Frank H. Büttner, Sandra Handschuh, Markus Zeeb, Rainer Walter |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
musculoskeletal diseases endocrine system diseases Biochemistry lcsh:Chemistry 03 medical and health sciences 0302 clinical medicine Tetramer Materials Chemistry medicine Environmental Chemistry Endothelial dysfunction Mode of action Receptor biology integumentary system Chemistry Lectin Cancer food and beverages General Chemistry medicine.disease Small molecule Cell biology 030104 developmental biology lcsh:QD1-999 030220 oncology & carcinogenesis LDL receptor biology.protein lipids (amino acids peptides and proteins) |
Zdroj: | Communications Chemistry, Vol 3, Iss 1, Pp 1-11 (2020) |
ISSN: | 2399-3669 |
Popis: | The C-type lectin family member lectin-like oxidized LDL receptor-1 (LOX-1) has been object of intensive research. Its modulation may offer a broad spectrum of therapeutic interventions ranging from cardiovascular diseases to cancer. LOX-1 mediates uptake of oxLDL by vascular cells and plays an important role in the initiation of endothelial dysfunction and its progression to atherosclerosis. So far only a few compounds targeting oxLDL-LOX-1 interaction are reported with a limited level of characterization. Here we describe the identification and characterization of BI-0115, a selective small molecule inhibitor of LOX-1 that blocks cellular uptake of oxLDL. Identified by a high throughput screening campaign, biophysical analysis shows that BI-0115 binding triggers receptor inhibition by formation of dimers of the homodimeric ligand binding domain. The structure of LOX-1 bound to BI-0115 shows that inter-ligand interactions at the receptor interfaces are key to the formation of the receptor tetramer thereby blocking oxLDL binding. Lectin-like oxidised LDL receptor 1, LOX-1, is implicated in cardiovascular diseases and cancer. Here a small molecule inhibitor of LOX-1 is introduced, which in a unique mode of action stabilises dimers of LOX-1 to prevent LOX-1 mediated signalling. |
Databáze: | OpenAIRE |
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