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TitleStructural insights into ligand recognition, selectivity, and activation of bombesin receptor subtype-3.
Journal, issue, pagesCell Rep, Vol. 43, Issue 8, Page 114511, Year 2024
Publish dateAug 27, 2024
AuthorsChangyao Li / Youwei Xu / Wenxin Su / Xinheng He / Jingru Li / Xinzhu Li / H Eric Xu / Wanchao Yin /
PubMed AbstractBombesin receptor subtype-3 (BRS3) is an important orphan G protein-coupled receptor that regulates energy homeostasis and insulin secretion. As a member of the bombesin receptor (BnR) family, the ...Bombesin receptor subtype-3 (BRS3) is an important orphan G protein-coupled receptor that regulates energy homeostasis and insulin secretion. As a member of the bombesin receptor (BnR) family, the lack of known endogenous ligands and high-resolution structure has hindered the understanding of BRS3 signaling and function. We present two cryogenic electron microscopy (cryo-EM) structures of BRS3 in complex with the heterotrimeric G protein in its active states: one bound to the pan-BnR agonist BA1 and the other bound to the synthetic BRS3-specific agonist MK-5046. These structures reveal the architecture of the orthosteric ligand pocket underpinning molecular recognition and provide insights into the structural basis for BRS3's selectivity and low affinity for bombesin peptides. Examination of conserved micro-switches suggests a shared activation mechanism among BnRs. Our findings shed light on BRS3's ligand selectivity and signaling mechanisms, paving the way for exploring its therapeutic potential for diabetes, obesity, and related metabolic disorders.
External linksCell Rep / PubMed:39024101
MethodsEM (single particle)
Resolution2.9 - 2.93 Å
Structure data

EMDB-38928, PDB-8y52:
Cryo-EM structure of the BA1-bound BRS3-Gq complex
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-38929, PDB-8y53:
Cryo-EM structure of the MK-5046-bound BRS3-Gq complex
Method: EM (single particle) / Resolution: 2.93 Å

Chemicals

PDB-1d54:
ANTHRACYCLINE BINDING TO DNA: HIGH RESOLUTION STRUCTURE OF D(TGTACA) COMPLEXED WITH 4'-EPIADRIAMYCIN

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • lama glama (llama)
KeywordsMEMBRANE PROTEIN / GPCR / Bombesin receptor subtype-3 receptor / BA1 / MEMBRANE PROTEIN/IMMUNE SYSTEM / MK-5046 / MEMBRANE PROTEIN-IMMUNE SYSTEM complex

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