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Dual Action Calcium-Sensing Receptor Modulator Unmasks Novel Mode-Switching Mechanism

Karen J Gregory1, Irina Kufareva2, Andrew N Keller1

  • 1Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Monash University, Parkville, Victoria 3052, Australia.

ACS Pharmacology & Translational Science
|March 29, 2020
PubMed

Insights

Negative allosteric modulators (NAMs) targeting the calcium-sensing receptor (CaSR) exhibit mode-switching behavior. This CaSR NAM can potentiate or inhibit receptor activity, offering new therapeutic strategies.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Structural Biology

Background:

  • Negative allosteric modulators (NAMs) of the calcium-sensing receptor (CaSR) have shown limited success in osteoporosis but are being explored for hypocalcemic and inflammatory lung diseases.
  • The precise mechanisms by which CaSR NAMs inhibit responses to endogenous activators remain incompletely understood.
  • Developing a deeper mechanistic insight into CaSR negative allosteric modulation is crucial for designing improved CaSR-targeting therapeutics.

Purpose of the Study:

  • To elucidate the mechanistic and structural basis of allosteric modulation by the CaSR NAM, calhex231.
  • To investigate how calhex231 interacts with the CaSR dimer to influence receptor activity.
  • To explore the implications of novel allosteric modulation mechanisms for CaSR-targeting drug discovery.

Main Methods:

  • Utilized biochemical assays to assess the activity of CaSR in the presence of calhex231 and various agonists.
  • Employed structural biology techniques to determine the binding modes of calhex231 within the CaSR dimer.
  • Analyzed the functional consequences of calhex231 occupying one versus both protomers of the CaSR dimer.

Main Results:

  • Demonstrated that calhex231 exhibits mode-switching behavior, acting as a potentiator or inhibitor of CaSR activity.
  • Showed that the effect of calhex231 is dependent on its binding stoichiometry within the CaSR dimer (one or both protomers).
  • Identified a novel mechanism of allosteric modulation involving differential protomer occupancy in a Class C G protein-coupled receptor.

Conclusions:

  • Calhex231 displays a unique mode-switching mechanism at the CaSR, challenging previous assumptions about NAM function.
  • This discovery provides a new framework for understanding CaSR allosteric modulation.
  • The findings have significant implications for the rational design of next-generation CaSR-targeting drugs with enhanced therapeutic potential.

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