AI Article Synopsis
- Niacin, a longstanding lipid-lowering medication, interacts with the hydroxycarboxylic acid receptor 2 (HCAR2) but has negative side effects like skin flushing.
- New HCAR2 agonists, such as MK-6892 and GSK256073, aim to reduce these side effects, although the specifics of how they activate HCAR2 remains unclear.
- This study utilized cryoelectron microscopy to reveal how different ligands bind to HCAR2, showing that their effects depend on specific amino acids, providing essential knowledge for the development of HCAR2-targeted therapies.
Article Abstract
Niacin, an age-old lipid-lowering drug, acts through the hydroxycarboxylic acid receptor 2 (HCAR2), a G-protein-coupled receptor (GPCR). Yet, its use is hindered by side effects like skin flushing. To address this, specific HCAR2 agonists, like MK-6892 and GSK256073, with fewer adverse effects have been created. However, the activation mechanism of HCAR2 by niacin and these new agonists is not well understood. Here, we present three cryoelectron microscopy structures of Gi-coupled HCAR2 bound to niacin, MK-6892, and GSK256073. Our findings show that different ligands induce varying binding pockets in HCAR2, influenced by aromatic amino acid clusters (W91, H161, W188, H189, and F193) from receptors ECL1, TM4, and TM5. Additionally, conserved residues R111 and Y284, unique to the HCA receptor family, likely initiate activation signal propagation in HCAR2. This study provides insights into ligand recognition, receptor activation, and G protein coupling mediated by HCAR2, laying the groundwork for developing HCAR2-targeted drugs.
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| http://dx.doi.org/10.1016/j.celrep.2023.113406 | DOI Listing |
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