Marianne Mühlbacher1, Prof. Dr. Norbert Sträter1
1Universität Leipzig, Leipzig, Germany
marianne.muehlbacher@bbz.uni-leipzig.de
The calcium-sensing receptor (CaSR) and the sweet and umami taste receptors (T1R) belong to class C of GPCRs and have a venus flytrap domain (VFD) and a cysteine-rich region (CRR) at their N-terminus. While the CaSR forms a homodimer, the T1R receptors are heterodimers. The CaSR is best known for its role in calcium homeostasis, but it is also involved in taste sensing (Sato et al. 2022). Taste receptors on the other hand are to date mostly known for being responsible for taste sensing, giving organisms the ability to differentiate between sources of nutrition and potentially poisonous food (Töle et al. 2019). But they are also expressed in other tissues, like the upper airways and there has been recent research that the T1Rs function as chemoreceptors in the respiratory system, heart and intestine (Servant and Frerot 2021; Lee et al. 2014). The CaSR ectodomain structure has been determined by Geng et al. (2016) and Zhang et al. (2016). While the binding pocket for amino acids and small peptides is well characterized, only one binding site for Ca2+ ions has been unambiguously identified per protomer. Since the CaSR displays cooperative calcium binding with Hill coefficients larger than 2 in many studies, it is likely that more bindings sites for calcium ions exist. We are trying to identify such additional binding sites by a variation of calcium ion concentration and detection of the ions by anomalous scattering at long wavelength. Of particular interest is also the allosteric modulation of the CaSR, for treatment of hyperparathyroidism and parathyroid carcinoma. Two drugs that target the CaSR are currently on the market, cinacalcet and etelcalcetide. Both are allosteric activators and mimick the action of calcium ions. It is also known that aromatic amino acids, specifically L-tryptophane, show a high affinity to the protein (Sato et al. 2022). Therefore, small molecules with a structure mimicking L-Trp are investigated for binding. On the other hand no drugs blocking the CaSR have shown sufficient results yet (Nemeth and Shoback 2013). Structure-based ligand development can therefore be used to identify new modulators binding to the venus flytrap domain.
To date there are no crystal structures of the human T1Rs known. As expression is proving difficult, in silico docking studies using alphafold multimer predictions (Evans et al. 2021) will be carried out. T1Rs have been reported to regulate antimicrobial peptide production. (Lee et al. 2014).
Keywords: calcium-sensing receptor; sweet and umami taste receptors; GPCRs, venus-flytrap domain