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Instruments / Technical Area	Publication Details	Published	Actions
I24-Microfocus Macromolecular Crystallography	Structural insights into the human niacin receptor HCA2-Gi signalling complex Yang Yang , Hye Jin Kang , Ruogu Gao , Jingjing Wang , Gye Won Han , Jeffrey F. Diberto , Lijie Wu , Jiahui Tong , Lu Qu , Yiran Wu , Ryan Pileski , Xuemei Li , Xuejun Cai Zhang , Suwen Zhao , Terry Kenakin , Quan Wang , Raymond C. Stevens , Wei Peng , Bryan L. Roth , Zihe Rao , Zhi-Jie Liu Nature Communications 14 DOI: 10.1038/s41467-023-37177-6 Open Access Show Abstract ▼ 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-Gi 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.	Mar 2023
I24-Microfocus Macromolecular Crystallography	Crystal Structure of the Human Cannabinoid Receptor CB2 Xiaoting Li , Tian Hua , Kiran Vemuri , Jo-Hao Ho , Yiran Wu , Lijie Wu , Petr Popov , Othman Benchama , Nikolai Zvonok , K’ara Locke , Lu Qu , Gye Won Han , Malliga R. Iyer , Resat Cinar , Nathan J. Coffey , Jingjing Wang , Meng Wu , Vsevolod Katritch , Suwen Zhao , George Kunos , Laura M. Bohn , Alexandros Makriyannis , Raymond C. Stevens , Zhi-Jie Liu Cell DOI: 10.1016/j.cell.2018.12.011 Show Abstract ▼ Abstract: The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257’s unexpected opposing functional profile of CB2 antagonism versus CB1 agonism. Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system.	Jan 2019

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