具有偏向变构调节剂的复合物揭示了神经降压素受体变构,Biochemistry

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具有偏向变构调节剂的复合物揭示了神经降压素受体变构
Biochemistry ( IF 2.9 ) Pub Date : 2023-03-14 , DOI: 10.1021/acs.biochem.3c00029
Brian E Krumm ₁ , Jeffrey F DiBerto ₁ , Reid H J Olsen ₁ , Hye Jin Kang _{1,

2} , Samuel T Slocum _{1,

2} , Shicheng Zhang ₁ , Ryan T Strachan ₁ , Xi-Ping Huang _{1,

2} , Lauren M Slosky ₃ , Anthony B Pinkerton ₄ , Lawrence S Barak ₅ , Marc G Caron _{5,

6} , Terry Kenakin ₁ , Jonathan F Fay ₇ , Bryan L Roth _{1,

2,

8}

Affiliation

Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599-7365, United States.
National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599-7365, United States.
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, United States.
Department of Cell Biology, Duke University, Durham, North Carolina 27710, United States.
Departments of Medicine and Neurobiology, Duke University, Durham, North Carolina 27710, United States.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599, United States.
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, United States.

NTSR1 神经降压素受体 (NTSR1) 是一种在大脑和外周组织中发现的 G 蛋白偶联受体 (GPCR)，神经降压素 (NTS) 是其内源性肽配体。在大脑中，NTS 调节多巴胺神经元活动，诱导非阿片类药物依赖性镇痛，并调节食物摄入。最近的研究表明，将 NTSR1 偏向 β-arrestin 信号传导可以减弱精神兴奋剂和其他滥用药物的作用。在这里，我们提供了 NTSR1 三元复合物与异三聚体 Gq 和 GoA 的冷冻电镜结构，有或没有脑渗透小分子 SBI-553。在功能研究中，我们发现 SBI-553 表现出复杂的变构作用，例如对 G 蛋白（Gα 亚基选择性）的负变构调节以及对 NTSR1 β-arrestin 易位的正变构调节和激动作用。变构结合位点的详细结构分析阐明了 SBI-553 对 NTSR1 的偏向变构调节的结构决定因素。

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更新日期：2023-03-14

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