Volume 33, No 1, Jan 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 1, January 2023: 46-54

ORIGINAL ARTICLES

Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1

Ping Luo^1,† , Wenbo Feng^2,† , Shanshan Ma¹ , Antao Dai³ , Kai Wu¹ , Xianyue Chen⁴ , Qingning Yuan¹ , Xiaoqing Cai³ , Dehua Yang^3,4,5 , Ming-Wei Wang^2,3,4,5,* , H. Eric Xu^1,5,6,7,* , Yi Jiang^6,8,*

¹The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
²Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China
³The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
⁴Research Center for Deepsea Bioresources, Sanya, Hainan, China
⁵University of Chinese Academy of Sciences, Beijing, China
⁶School of Life Science and Technology, ShanghaiTech University, Shanghai, China
⁷State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
⁸Lingang Laboratory, Shanghai, China
^†These authors contributed equally: Ping Luo, Wenbo Feng
Correspondence: Ming-Wei Wang(mwwang@simm.ac.cn)H. Eric Xu(eric.xu@simm.ac.cn)Yi Jiang(yjiang@lglab.ac.cn)

G protein-coupled receptors (GPCRs) are regulated by various downstream proteins, of which the melanocortin receptor accessory protein 1 (MRAP1) is closely involved in the regulation of melanocortin receptor 2 (MC2R). Assisted by MRAP1, MC2R responds to adrenocorticotropic hormone (ACTH) and stimulates glucocorticoid biogenesis and cortisol secretion. MC2R activation plays an essential role in the hypothalamic-pituitary-adrenal (HPA) axis that regulates stress response, while its dysfunction causes glucocorticoid insufficiency- or cortisol excess-associated disorders. Here, we present a cryo-electron microscopy (cryo-EM) structure of the ACTH-bound MC2R–Gs–MRAP1 complex. Our structure, together with mutagenesis analysis, reveals a unique sharp kink at the extracellular region of MRAP1 and the ‘seat-belt’ effect of MRAP1 on stabilizing ACTH binding and MC2R activation. Mechanisms of ACTH recognition by MC2R and receptor activation are also demonstrated. These findings deepen our understanding of GPCR regulation by accessory proteins and provide valuable insights into the ab initio design of therapeutic agents targeting MC2R.

https://doi.org/10.1038/s41422-022-00751-6

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