Mechanisms of ligand binding and activation at the PTHR1

甲状旁腺激素（PTH）/PTH相关蛋白（PTHrP）受体 （PTHR 1）在骨骼发育和维持钙和 磷酸盐稳态PTHR 1通过结合两种不同的 多肽激素配体- PTHrP和PTH。PTHR 1具有较高的医学 由于其与骨质疏松症、甲状旁腺功能减退症等疾病有关， 和詹森干骺端软骨发育不良这使得PTHR 1成为重要的 治疗干预目标。开发针对PTHR 1的有效药物是 然而，这是具有挑战性的，尤其是通过合理的设计方法。目前的几种药物 PTHR 1的可用性并不理想。对于骨质疏松症，两种可用的药物： 重组PTH（1-34），forteo，和合成的PTHrP（1-34）类似物，abaloparthine， 改善骨参数，但效用受到诸如需要每日 注射，因为如果口服，肽会被肠道蛋白酶破坏， 潜在的不良反应，如过量骨吸收和高钙血症，以及 随着时间的推移，合成代谢的功效逐渐减弱。更好地理解分子 因此，配体与PTHR 1结合并激活信号传导的机制是 需要促进设计更有效的基于PTHR 1的疗法，特别是 那些是口服的。这里提出的研究旨在揭示这些新的方面， PTHR 1机制，从而确定肽以及小分子如何结合到 这种G蛋白偶联受体并诱导靶细胞中的选择性信号应答 最终改善人类健康。 !

Abstract The parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor (PTHR1) plays vital roles in bone development and in maintaining calcium and phosphate homeostasis. The PTHR1 mediates these roles by binding two distinct polypeptide hormone ligands - PTHrP and PTH. The PTHR1 is of high medical importance as it is associated with diseases such as osteoporosis, hypoparathyroidism and Jansen's metaphyseal chondrodysplasia. This makes the PTHR1 an important target for therapeutic interventions. Developing effective drugs for the PTHR1 is challenging, however, especially by rational design approaches. The few drugs currently available for the PTHR1 are not ideal. For osteoporosis, the two available drugs: recombinant PTH(1-34), forteo, and a synthetic PTHrP(1-34) analog, abaloparatide, improve bone parameters but utility is limited by factors such as the need for daily injection, as the peptides would be destroyed by gut proteases if taken orally, the potential for adverse effects, such as excess bone resorption and hypercalcemia, and a waning of anabolic efficacy over time. A better understanding of the molecular mechanisms by which ligands bind to the PTHR1 and activate signaling is therefore needed to facilitate the design of more effective PTHR1-based therapies, particularly ones that are orally active. The studies proposed here aim to reveal such new aspects of PTHR1 mechanisms, and to thus define how peptides as well as small-molecules bind to this G protein-coupled receptor and induce selective signaling responses in target cells that ultimately lead to improvements in human health. !