Structural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2

Abstract

Hydroxycarboxylic acid receptors (HCAR1, HCAR2, and HCAR3) transduce Gi/o signaling upon biding to molecules such as lactic acid, butyric acid and 3-hydroxyoctanoic acid, which are associated with lipolytic and atherogenic activity, and neuroinflammation. Although many reports have elucidated the function of HCAR2 and its potential as a therapeutic target for treating not only dyslipidemia but also neuroimmune disorders such as multiple sclerosis and Parkinson’s disease, the structural basis of ligand recognition and ligand-induced Gi-coupling remains unclear. Here we report three cryo-EM structures of the human HCAR2–Gi signaling complex, each bound with different ligands: niacin, acipimox or GSK256073. All three agonists are held in a deep pocket lined by residues that are not conserved in HCAR1 and HCAR3. A distinct hairpin loop at the HCAR2 N-terminus and extra-cellular loop 2 (ECL2) completely enclose the ligand. These structures also reveal the agonist-induced conformational changes propagated to the G-protein-coupling interface during activation. Collectively, the structures presented here are expected to help in the design of ligands specific for HCAR2, leading to new drugs for the treatment of various diseases such as dyslipidemia and inflammation.

Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode

“…2F), which is also the case for the six structures in complex with niacin and the two with MMF, although niacin is proposed to bind in two different conformations (Fig. 2B) 12,13,16,18,19 . However, for GSK356073, two very different poses were reported where either one or the other of its ketone groups are interacting with Arg111 3.36 , which positions the 8-chloro and the pentyl group of GSK356073 in two very different places in the pocket (Fig.…”

“…In six of these papers, the binding pose of MK6892 was confirmed [13][14][15][17][18][19] and in five papers the binding pose of niacin in the central orthosteric pocket between TM-II,-III, -V, and -VII covered by ECL-2b was confirmed (Fig. 2B) 12,13,16,18,19 . This pocket wasas expected-shown also to be the binding site for other small synthetic agonists: Acifran (Fig.…”

“…In the weeks before and after the publication of Yang et al eight other reports were submitted each presenting one to five HCAR2 cryo-EM structures [12][13][14][15][16][17][18][19] (Table 1). In six of these papers, the binding pose of MK6892 was confirmed [13][14][15][17][18][19] and in five papers the binding pose of niacin in the central orthosteric pocket between TM-II,-III, -V, and -VII covered by ECL-2b was confirmed (Fig.…”

Medicinal Chemistry of Drugs with N-Oxide Functionalities

“…Acipimox (Figure ) is a medication for hyperlipidemic patients that are unresponsive to alternative therapeutic approaches. It inhibits lipolysis and restricts the flow of free fatty acids to the liver via binding to the G-protein-coupled receptor HCAR2 on adipocytes . This leads to a reduction in the precursor pool size of the very low-density lipoprotein (VLDL)-triglyceride.…”

“…It inhibits lipolysis and restricts the flow of free fatty acids to the liver via binding to the G-protein-coupled receptor HCAR2 on adipocytes. 107 This leads to a reduction in the precursor pool size of the very low-density lipoprotein (VLDL)-triglyceride. It inhibits VLDL synthesis, and consequently lowers plasma triglyceride levels while elevating high-density lipoprotein (HDL).…”