The calcium-sensing receptor (CaSR), a cell surface sensor for Ca 2+ , is the master regulator of calcium homeostasis in humans and is targeted by calcimimetic drugs for the treatment of parathyroid disorders 1 . CaSR is a family C G protein-coupled receptor (GPCR) 2 that functions as an obligate homodimer with each protomer comprised of a Ca 2+ -binding extracellular domain (ECD) and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins.Here we show cryo-electron microscopy (cryo-EM) structures of near full-length human CaSR in inactive or active states bound to Ca 2+ and various calcilytic or calcimimetic drug molecules. We show that upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G protein-coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor.
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The human histamine H3 receptor (hH3R) is
predominantly expressed in the CNS, where it regulates the synthesis
and release of histamine and other neurotransmitters. Due to its neuromodulatory
role, the hH3R has been associated with various CNS disorders,
including Alzheimer’s and Parkinson’s disease. Markedly,
the hH3R gene undergoes extensive splicing, resulting in
20 isoforms, of which 7TM isoforms exhibit variations in the intracellular
loop 3 (IL3) and/or C-terminal tail. Particularly, hH3R
isoforms that display variations in IL3 (e.g., hH3R-365)
are shown to differentially signal via Gαi-dependent
pathways upon binding of biased agonists (e.g., immepip, proxifan,
imetit). Nevertheless, the mechanisms underlying biased agonism at
hH3R isoforms remain unknown. Using a structure–function
relationship study with a broad range of H3R agonists,
we thereby explored determinants underlying isoform bias at hH3R isoforms that exhibit variations in IL3 (i.e., hH3R-445, -415, -365, and -329) in a Gαi-dependent
pathway (cAMP inhibition). Hence, we systematically characterized
hH3R isoforms on isoform bias by comparing various ligand
properties (i.e., structural and molecular) to the degree of isoform
bias. Importantly, our study provides novel insights into the structural
and molecular basis of receptor isoform bias, highlighting the importance
to study GPCRs with multiple isoforms to better tailor drugs.
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