Chunyu Wang, Yongfeng Liu, Marion Lanier, Adam Yeager, Isha Singh, Ryan H Gumpper, Brian E Krumm, Chelsea DeLeon, Shicheng Zhang, Marcus Boehm, Richard Pittner, Alain Baron, Lisa Dvorak, Corinne Bacon, Brian K Shoichet, Esther Martinborough, Jonathan F Fay, Can Cao, Bryan L Roth
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引用次数: 0
摘要
人类 MRGPRD 蛋白是 Mas 相关 G 蛋白偶联受体（MRGPRs）中的一种，它参与痛觉、痒觉和其他炎症刺激的感应。与其他 MRGPRs 一样，MRGPRD 也是一种研究相对不足的受体，已知的激动剂很少。迄今报道的最有效的 MRGPRD 小分子激动剂是 β-丙氨酸，其亲和力在微摩尔范围内，这在很大程度上限制了对其功能的研究。在此，我们报告了两种MRGPRD激动剂EP-2825和EP-3945，它们的效力大约是β-丙氨酸的100倍，并分别测定了与EP-2825和EP-3945复合的MRGPRD-Gq的结构。这些结构揭示了 MRGPRD 不同的激动剂结合模式以及正交口袋的巨大构象可塑性。总之，高亲和力 MRGPRD 激动剂及其不同结合模式的发现将有助于针对这一研究不足的受体进行功能研究和基于结构的配体设计。
High-affinity agonists reveal recognition motifs for the MRGPRD GPCR.
The human MRGPRD protein is a member of the Mas-related G protein-coupled receptors (MRGPRs) that is involved in the sensing of pain, itch, and other inflammatory stimuli. As with other MRGPRs, MRGPRD is a relatively understudied receptor with few known agonists. The most potent small-molecule agonist of MRGPRD reported so far is β-alanine, with an affinity in the micromole range, which largely restricts its functional study. Here, we report two MRGPRD agonists, EP-2825 and EP-3945, that are approximately 100-fold more potent than β-alanine and determine the structures of MRGPRD-Gq in complex with EP-2825 and EP-3945, respectively. The structures reveal distinct agonist binding modes of MRGPRD and large conformational plasticity of the orthosteric pocket. Collectively, the discovery of high-affinity MRGPRD agonists and their distinct binding modes will facilitate the functional study and the structure-based design of ligands targeting this understudied receptor.
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Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted.
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