AI Article Synopsis
- Niacin, an agonist of the hydroxycarboxylic acid receptor 2 (HCA2), has been used for a long time to treat dyslipidemia but commonly causes skin flushing as a side effect.
- Researchers have been trying to find new HCA2-targeting agents that lower lipids without adverse effects, although the exact signaling mechanisms of HCA2 have not been well understood.
- This study presents the detailed structures of HCA2-G complexed with the agonist MK-6892 and in its inactive state, shedding light on how HCA2 activates and signals, which could help in developing new treatments targeting this receptor.
Article Abstract
The hydroxycarboxylic acid receptor 2 (HCA2) agonist niacin has been used as treatment for dyslipidemia for several decades albeit with skin flushing as a common side-effect in treated individuals. Extensive efforts have been made to identify HCA2 targeting lipid lowering agents with fewer adverse effects, despite little being known about the molecular basis of HCA2 mediated signalling. Here, we report the cryo-electron microscopy structure of the HCA2-G signalling complex with the potent agonist MK-6892, along with crystal structures of HCA2 in inactive state. These structures, together with comprehensive pharmacological analysis, reveal the ligand binding mode and activation and signalling mechanisms of HCA2. This study elucidates the structural determinants essential for HCA2 mediated signalling and provides insights into ligand discovery for HCA2 and related receptors.
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Source |
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10043007 | PMC |
| http://dx.doi.org/10.1038/s41467-023-37177-6 | DOI Listing |
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