Ca(2+)/Sr(2+) Selectivity in Calcium-Sensing Receptor (CaSR): Implications for Strontium's Anti-Osteoporosis Effect.
Ca(2+)/Sr(2+) Selectivity in Calcium-Sensing Receptor (CaSR): Implications for Strontium's Anti-Osteoporosis Effect.
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DOI：
10.3390/biom11111576
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发表时间：
2021-10-24
期刊：
影响因子：
5.5
通讯作者：
Dudev T
中科院分区：
文献类型：
--
作者：
Cheshmedzhieva D;Ilieva S;Permyakov EA;Permyakov SE;Dudev T
细胞外钙敏感受体（CaSR）控制重要的骨细胞功能，例如细胞生长、分化和凋亡。天然激动剂 (Ca2+) 与 CaSR 的结合会激活受体，受体会发生结构变化，从而触发细胞信号传导通路上的一系列事件。锶（以可溶性盐的形式）也被发现是一种 CaSR 激动剂。 Sr2+ 受体的激活被认为是锶发挥其抗骨质疏松作用的主要机制，主要针对绝经后妇女。锶激活的 CaSR 启动一系列信号转导事件，导致破骨细胞凋亡和成骨细胞分化，从而强化骨组织。 Sr2+ 激活 CaSR 的内在机制仍然是个谜。因此，通过结合密度泛函理论（DFT）计算和极化连续介质模型（PCM）计算，我们发现活化的CaSR中的Ca2+结合位点1、3和4虽然具有不同数量和类型的蛋白质配体、整体结构和电荷状态，但对Ca2+的选择性均高于Sr2+。如果这三个结合位点具有灵活性并且对引入的 Sr2+ 没有几何限制，则无论其结构差异如何，它们都表现出几乎相同的金属选择性。与 Ca2+ 和 Sr2+ 相比，Mg2+ 结构在优化过程中允许完全松弛时，采用其严格的六配位八面体结构，但代价是分离单主链羰基配体并将其转移到金属的第二配位层。 Mg2+ 和 Sr2+ 与刚性/非柔性钙设计的结合袋的结合需要结合离子的额外能量损失；然而，这样做的代价（由Sr2+支付）比Mg2+低得多。获得的结果描绘了控制金属阳离子之间对受体竞争的关键因素，并揭示了锶治疗作用的某些方面。
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.
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