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Structural insights into physiological activation and antagonism of melanin-concentrating hormone receptor MCHR1
Open accessPreprint — published as 10.1038/s41421-024-00754-0
Abstract
Melanin-concentrating hormone (MCH) is a 19-amino-acid neuropeptide playing crucial roles in energy homeostasis, sleep, and various physiological processes. It acts through two G protein-coupled receptors, MCHR1 and MCHR2, with MCHR1 being universally present in mammals and a potential target for treating metabolic and mental health conditions. However, drug development efforts have been impeded by the lack of structural information. Here, we present the cryo-EM structures of MCHR1 in its active state complexed with MCH and G i1 , as well as in its inactive state bound to a selective antagonist SNAP-94847. Structural and mutagenesis analyses disclosed the recognition mechanisms for both MCH and SNAP-94847, the activation mechanism and antagonism of MCHR1, and the determinants of ligand specificity. These findings are expected to accelerate the development of better drugs targeting the MCH system.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Ye, X., Liu, G., Li, X., He, B., Tao, Y., Liu, H., & Gong, W.
- Affiliations
- University of Science and Technology of China (CN)
- Corresponding author
- Liu, Haiping
- Gong, Weimin
- Venue
- Cell Discovery
- Publisher
- openRxiv
- Published
- 2024-03-12
- Volume
- 10
- Issue
- 1
- Pages
- 124-124
- ISSN
- 2056-5968 (ISSN-L)
- PMC
- PMC11608246
- OpenAlex
- W4404874705
- Cited by
- 3
- References
- 1
- Citations by year
- 2026: 2 · 2025: 1
- FWCI
- 0.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Cell Discovery (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (XDB0540000, T2221005)
- Ministry of Science and Technology of the People's Republic of China (2021YFA0910202)
- University of Science and Technology of China
- University of Chinese Academy of Sciences (XDB0540000)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- melanin-concentrating hormone receptor 1, melanin-concentrating hormone, G protein-coupled receptors, receptor activation, receptor antagonism, ligand binding, receptor structure, obesity, sleep disorders
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