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  3. Photo-cross-linking-assisted deorphanization deciphers GPR50-L-LEN pairing in metabolism

Photo-cross-linking-assisted deorphanization deciphers GPR50-L-LEN pairing in metabolism

  • Nat Chem Biol. 2026 Jan 6. doi: 10.1038/s41589-025-02098-6.
Rui Wu # 1 2 3,  Na Li # 2 3 4,  Zhihui Wen # 5 6,  Ya Wang 2 3,  Shitian Li 2 3,  Hao Zhou 2 3 5,  Yuehong Huang 2 3 4,  Xiao Xie 5 6,  Xiaoyun Zhao 1,  Xiaohui Wang 2 3 4,  Shaoxin Tao 7,  Guoliang Chai 7,  Tongfei A Wang 2 3,  Zhen Li 8 9 10,  Peng R Chen 11 12,  Miao Jing 13 14 15 16
Affiliations

Affiliations

  • 1 College of Biological Science, China Agricultural University, Beijing, China.
  • 2 Beijing Institute for Brain Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3 Chinese Institute for Brain Research, Beijing, China.
  • 4 School of Basic Medical Sciences, Capital Medical University, Beijing, China.
  • 5 Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
  • 6 Synthetic and Functional Biomolecules Center, Department of Chemical Biology, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
  • 7 Department of Neurology, National Center for Neurological Disorders, Xuanwu Hospital Capital Medical University, Beijing, China.
  • 8 College of Biological Science, China Agricultural University, Beijing, China. [email protected].
  • 9 Beijing Institute for Brain Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 10 Chinese Institute for Brain Research, Beijing, China. [email protected].
  • 11 Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. [email protected].
  • 12 Synthetic and Functional Biomolecules Center, Department of Chemical Biology, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China. [email protected].
  • 13 College of Biological Science, China Agricultural University, Beijing, China. [email protected].
  • 14 Beijing Institute for Brain Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 15 Chinese Institute for Brain Research, Beijing, China. [email protected].
  • 16 School of Basic Medical Sciences, Capital Medical University, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41495223 DOI: 10.1038/s41589-025-02098-6
Abstract

G-protein-coupled receptors (GPCRs) are transmembrane proteins that transduce extracellular stimuli into intracellular events. While central to physiology and drug discovery, approximately 100 GPCRs remain orphan, limiting insights into their biology. We establish a generalizable photo-cross-linking-assisted GPCR deorphanization platform that leverages site-specifically incorporated photo-cross-linkers for interface-selective ligand capture from native biological samples. We systematically demonstrate the sensitivity, specificity and broad applicability of our system using multiple GPCR-ligand pairs and further deorphanize GPR50 with the neuropeptide Little-LEN (L-LEN) as its endogenous ligand. L-LEN selectively binds GPR50 and modulates cellular activities through downstream Gαi signaling in tissue. In behaving mice, L-LEN functionally coordinates with GPR50 to regulate energy expenditure and thermogenesis, mechanistically through brain-adipose cross-talk, whereas their deficiency increased the likelihood of torpor following challenges. In summary, we develop an efficient platform for GPCR deorphanization from native samples, and the deorphanization of GPR50 provides insights into its function and drug discovery.

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