Mechanisms of ligand binding and activation at the PTHR1

摘要甲状旁腺激素/甲状旁腺激素相关蛋白受体 (PTHR1)在骨骼发育、维持钙和 磷酸盐平衡。PTHR1通过结合两个不同的 多肽激素配体-甲状旁腺素和甲状旁腺素。PTHR1具有很高的医学价值 重要性，因为它与骨质疏松症、甲状旁腺功能减退症等疾病有关 和詹森的干骺端软骨发育不良。这使得PTHR1成为一个重要的 治疗干预的目标。正在为PTHR1开发有效的药物 然而，具有挑战性，特别是通过理性的设计方法。目前为数不多的药物 可供PTHR1使用的都不理想。对于骨质疏松症，有两种可用的药物： 重组PTH(1-34)，FORTEO，和合成的PTHrP(1-34)类似物，阿巴拉肽， 改善骨骼参数，但实用性受到日常需要等因素的限制 注射，由于口服多肽会被肠道蛋白酶破坏，因此 潜在的不良反应，如过度的骨吸收和高钙血症，以及 随着时间的推移，合成代谢的效力逐渐减弱。更好地理解分子 因此，配体与PTHR1结合并激活信号转导的机制 需要促进更有效的基于PTHR1的疗法的设计，特别是 有口服活性的。这里提出的研究旨在揭示这些新的方面 PTHR1机制，并由此定义多肽以及小分子如何与 这种G蛋白偶联受体在靶细胞中诱导选择性信号反应 这最终会改善人类健康。 好了！

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. !