Therapeutic Opportunities of Targeting Allosteric Binding Sites on the Calcium-Sensing Receptor

2021 ◽  
Vol 4 (2) ◽  
pp. 666-679
Author(s):  
Jiayin Diao ◽  
Aaron DeBono ◽  
Tracy M. Josephs ◽  
Jane E. Bourke ◽  
Ben Capuano ◽  
...  
Keyword(s):  
Binding Sites ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Allosteric Binding Sites

scholarly journals Ca2+/Sr2+ Selectivity in Calcium-Sensing Receptor (CaSR): Implications for Strontium’s Anti-Osteoporosis Effect

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1576
Author(s):  
Diana Cheshmedzhieva ◽  
Sonia Ilieva ◽  
Eugene A. Permyakov ◽  
Sergei E. Permyakov ◽  
Todor Dudev
Keyword(s):  
Binding Sites ◽  
Density Functional ◽  
Structural Changes ◽  
Binding Pocket ◽  
Bone Cell ◽  
Therapeutic Effects ◽  
Calcium Sensing Receptor ◽  
Additional Energy ◽  
Cell Functions ◽  
Calcium Sensing

The extracellular calcium-sensing receptor (CaSR) controls vital bone cell functions such as cell growth, differentiation and apoptosis. The binding of the native agonist (Ca2+) to CaSR activates the receptor, which undergoes structural changes that trigger a cascade of events along the cellular signaling pathways. Strontium (in the form of soluble salts) has been found to also be a CaSR agonist. The activation of the receptor by Sr2+ is considered to be the major mechanism through which strontium exerts its anti-osteoporosis effect, mostly in postmenopausal women. Strontium-activated CaSR initiates a series of signal transduction events resulting in both osteoclast apoptosis and osteoblast differentiation, thus strengthening the bone tissue. The intimate mechanism of Sr2+ activation of CaSR is still enigmatic. Herewith, by employing a combination of density functional theory (DFT) calculations and polarizable continuum model (PCM) computations, we have found that the Ca2+ binding sites 1, 3, and 4 in the activated CaSR, although possessing a different number and type of protein ligands, overall structure and charge state, are all selective for Ca2+ over Sr2+. The three binding sites, regardless of their structural differences, exhibit almost equal metal selectivity if they are flexible and have no geometrical constraints on the incoming Sr2+. In contrast to Ca2+ and Sr2+, Mg2+ constructs, when allowed to fully relax during the optimization process, adopt their stringent six-coordinated octahedral structure at the expense of detaching a one-backbone carbonyl ligand and shifting it to the second coordination layer of the metal. The binding of Mg2+ and Sr2+ to a rigid/inflexible calcium-designed binding pocket requires an additional energy penalty for the binding ion; however, the price for doing so (to be paid by Sr2+) is much less than that of Mg2+. The results obtained delineate the key factors controlling the competition between metal cations for the receptor and shed light on some aspects of strontium’s therapeutic effects.

scholarly journals Mapping of human autoantibody binding sites on the calcium-sensing receptor

2009 ◽  
Vol 25 (1) ◽  
pp. 132-140 ◽  
Author(s):  
E Helen Kemp ◽  
Nikos G Gavalas ◽  
Samia Akhtar ◽  
Kai JE Krohn ◽  
J Carl Pallais ◽  
...  
Keyword(s):  
Binding Sites ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

Abstract #543 Teriparatide-Induced Hypercalcemic Crisis in a Patient on Lithium: Overwhelming the Calcium Sensing Receptor

2018 ◽  
Vol 24 ◽  
pp. 130-131
Author(s):  
Pratibha Abraham ◽  
Muhammad Siddiqui ◽  
Deepashree Gupta ◽  
Stewart Albert
Keyword(s):  
Calcium Sensing Receptor ◽  
Hypercalcemic Crisis ◽  
Calcium Sensing
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