Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling
Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling
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DOI：
10.1210/en.2015-1726
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发表时间：
2016-01-01
期刊：
影响因子：
4.8
通讯作者：
Gardella, Thomas J.
中科院分区：
文献类型：
--
作者：
Hattersley, Gary;Dean, Thomas;Gardella, Thomas J.
甲状旁腺素受体1(PTHR1)介导两种内源性多肽配体PTH和PTHrP的作用，从而在骨生物学中发挥关键作用。基于其刺激骨形成的能力，PTH(1-34)肽片段目前被用于治疗骨质疏松症。Abaloparatide(ABL)是一种新型的人PTHrP(1-34)的合成类似物，有望成为一种新的骨质疏松症治疗方法，因为动物研究表明，它可以刺激骨形成，并减少伴随的骨吸收和高钙效应，与PTH(1-34)一样。最近的体外研究表明，某些PTH或PTHrP配体类似物可以区分两种高亲和力的PTHR1构象，R-0和RG，有效地与R-0结合导致细胞内信号反应延长和动物钙化反应延长，而选择性与RG结合则导致更多的瞬时反应。众所周知，间歇性的PTH配体作用有利于骨形成反应，而连续的配体作用有利于净的骨吸收/钙化反应，我们假设ABL比PTH(1-34)更有选择性地与RG和R-0 PTHR1构象结合，从而在细胞中诱导更多的瞬时信号反应。我们发现ABL确实比PTH(1-34)对RG构象有更大的选择性，并且由于这种RG偏向，ABL在表达PTHR1的细胞中介导了更多的瞬时cAMP反应。这些发现提供了一个可信的机制(即，通过RG选择性结合的瞬时信号)，可以帮助解释ABL对骨骼的有利合成代谢作用。
The PTH receptor type 1 (PTHR1) mediates the actions of two endogenous polypeptide ligands, PTH and PTHrP, and thereby plays key roles in bone biology. Based on its capacity to stimulate bone formation, the peptide fragment PTH (1-34) is currently in use as therapy for osteoporosis. Abaloparatide (ABL) is a novel synthetic analog of human PTHrP (1-34) that holds promise as a new osteoporosis therapy, as studies in animals suggest that it can stimulate bone formation with less of the accompanying bone resorption and hypercalcemic effects that can occur with PTH (1-34). Recent studies in vitro suggest that certain PTH or PTHrP ligand analogs can distinguish between two high-affinity PTHR1 conformations, R-0 and RG, and that efficient binding to R-0 results in prolonged signaling responses in cells and prolonged calcemic responses in animals, whereas selective binding to RG results in more transient responses. As intermittent PTH ligand action is known to favor the bone-formation response, whereas continuous ligand action favors the net bone-resorption/calcemic response, we hypothesized that ABL binds more selectively to the RG vs the R-0 PTHR1 conformation than does PTH (1-34), and thus induces more transient signaling responses in cells. We show that ABL indeed binds with greater selectivity to the RG conformation than does PTH (1-34), and as a result of this RG bias, ABL mediates more transient cAMP responses in PTHR1-expressing cells. The findings provide a plausible mechanism (ie, transient signaling via RG-selective binding) that can help account for the favorable anabolic effects that ABL has on bone.