8GY7

Cryo-EM structure of ACTH-bound melanocortin-2 receptor in complex with MRAP1 and Gs protein

Summary for 8GY7

• Entry DOI: 10.2210/pdb8gy7/pdb
• EMDB information: 34371
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-3,Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: melanocortin-2 receptor, mrap1, gpcr, acth, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 180141.73

Authors

Luo, P.,Feng, W.B.,Ma, S.S.,Dai, A.T.,Yuan, Q.N.,Wu, K.,Yang, D.H.,Wang, M.W.,Xu, H.E.,Jiang, Y. (deposition date: 2022-09-21, release date: 2023-01-11, Last modification date: 2025-07-02)

Primary citation

Luo, P.,Feng, W.,Ma, S.,Dai, A.,Wu, K.,Chen, X.,Yuan, Q.,Cai, X.,Yang, D.,Wang, M.W.,Eric Xu, H.,Jiang, Y.
Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1.
Cell Res., 33:46-54, 2023

PubMed Abstract: 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-G-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.

PubMed: 36588120
DOI: 10.1038/s41422-022-00751-6

Experimental method

ELECTRON MICROSCOPY (3.3 Å)