Yin Jie, Rosenbaum Daniel M
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Curr Top Behav Neurosci. 2017;33:1-15. doi: 10.1007/7854_2016_52.
The human orexin/hypocretin receptors (hOXR and hOXR) are G protein-coupled receptors (GPCRs) that mediate the diverse functions of the orexin/hypocretin neuropeptides. Orexins/hypocretins produced by neurons in the lateral hypothalamus stimulate their cognate GPCRs in multiple regions of the central nervous system to control sleep and arousal, circadian rhythms, metabolism, reward pathways, and other behaviors. Dysfunction of orexin/hypocretin signaling is associated with human disease, and the receptors are active targets in a number of therapeutic areas. To better understand the molecular mechanism of the orexin/hypocretin neuropeptides, high-resolution three-dimensional structures of hOXR and hOXR are critical. We have solved high-resolution crystal structures of both human orexin/hypocretin receptors bound to high-affinity antagonists. These atomic structures have elucidated how different small molecule antagonists bind with high potency and selectivity, and have also provided clues as to how the native ligands may associate with their receptors. The orexin/hypocretin receptor coordinates, now available to the broader academic and drug discovery community, will facilitate rational design of new therapeutics that modulate orexin/hypocretin signaling in humans.
人类食欲素/下丘脑泌素受体（hOXR1和hOXR2）是G蛋白偶联受体（GPCRs），介导食欲素/下丘脑泌素神经肽的多种功能。下丘脑外侧神经元产生的食欲素/下丘脑泌素刺激中枢神经系统多个区域的同源GPCRs，以控制睡眠与觉醒、昼夜节律、新陈代谢、奖赏通路及其他行为。食欲素/下丘脑泌素信号传导功能障碍与人类疾病相关，这些受体是多个治疗领域的活性靶点。为了更好地理解食欲素/下丘脑泌素神经肽的分子机制，hOXR1和hOXR2的高分辨率三维结构至关重要。我们已解析了与高亲和力拮抗剂结合的两种人类食欲素/下丘脑泌素受体的高分辨率晶体结构。这些原子结构阐明了不同小分子拮抗剂如何高效且选择性地结合，也为天然配体与其受体的结合方式提供了线索。如今更广泛的学术和药物研发群体可获取的食欲素/下丘脑泌素受体坐标，将有助于合理设计调节人类食欲素/下丘脑泌素信号传导的新型疗法。
