Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 96-109 |
| Number of pages | 14 |
| Journal | ACS Pharmacology and Translational Sciences |
| Volume | 1 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 12 Sep 2018 |
Keywords
- Calcium-sensing receptor
- calhex231
- Allosteric modulator
Cite this
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Dual Action Calcium-Sensing Receptor Modulator Unmasks Novel Mode-Switching Mechanism. / Gregory, Karen; Kufareva, Irina; Keller, Andrew N.; Khajehali, Elham; Mun, Hee-chang; Goolam, Mahvash Ayesha; Mason, Rebecca S; Capuano, Ben; Conigrave, Arthur; Christopoulos, Arthur; Leach, Katie.
In: ACS Pharmacology and Translational Sciences, Vol. 1, No. 2, 12.09.2018, p. 96-109.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Dual Action Calcium-Sensing Receptor Modulator Unmasks Novel Mode-Switching Mechanism
AU - Gregory, Karen
AU - Kufareva, Irina
AU - Keller, Andrew N.
AU - Khajehali, Elham
AU - Mun, Hee-chang
AU - Goolam, Mahvash Ayesha
AU - Mason, Rebecca S
AU - Capuano, Ben
AU - Conigrave, Arthur
AU - Christopoulos, Arthur
AU - Leach, Katie
PY - 2018/9/12
Y1 - 2018/9/12
N2 - Negative allosteric modulators (NAMs) of the human calcium-sensing receptor (CaSR) have previously failed to show efficacy in human osteoporosis clinical trials, but there is now significant interest in repurposing these drugs for hypocalcemic disorders and inflammatory lung diseases. However, little is known about how CaSR NAMs inhibit the response to endogenous activators. An improved understanding of CaSR negative allosteric modulation may afford the opportunity to develop therapeutically superior CaSR-targeting drugs. In an attempt to elucidate the mechanistic and structural basis of allosteric modulation mediated by the previously reported NAM, calhex231, we herein demonstrate that calhex231 actually potentiates or inhibits the activity of multiple CaSR agonists depending on whether it occupies one or both protomers in a CaSR dimer. These findings reveal a novel mechanism of mode-switching at a Class C G protein-coupled receptor that has implications for drug discovery and potential clinical utility.
AB - Negative allosteric modulators (NAMs) of the human calcium-sensing receptor (CaSR) have previously failed to show efficacy in human osteoporosis clinical trials, but there is now significant interest in repurposing these drugs for hypocalcemic disorders and inflammatory lung diseases. However, little is known about how CaSR NAMs inhibit the response to endogenous activators. An improved understanding of CaSR negative allosteric modulation may afford the opportunity to develop therapeutically superior CaSR-targeting drugs. In an attempt to elucidate the mechanistic and structural basis of allosteric modulation mediated by the previously reported NAM, calhex231, we herein demonstrate that calhex231 actually potentiates or inhibits the activity of multiple CaSR agonists depending on whether it occupies one or both protomers in a CaSR dimer. These findings reveal a novel mechanism of mode-switching at a Class C G protein-coupled receptor that has implications for drug discovery and potential clinical utility.
KW - Calcium-sensing receptor
KW - calhex231
KW - Allosteric modulator
U2 - 10.1021/acsptsci.8b00021
DO - 10.1021/acsptsci.8b00021
M3 - Article
VL - 1
SP - 96
EP - 109
JO - ACS Pharmacology and Translational Sciences
JF - ACS Pharmacology and Translational Sciences
SN - 2575-9108
IS - 2
ER -