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TitleStructural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists.
Journal, issue, pagesCell Discov, Vol. 9, Issue 1, Page 66, Year 2023
Publish dateJun 30, 2023
AuthorsWenjing Sun / Fan Yang / Huanhuan Zhang / Qingning Yuan / Shenglong Ling / Yuanxia Wang / Pei Lv / Zelin Li / Yifan Luo / Dongsheng Liu / Wanchao Yin / Pan Shi / H Eric Xu / Changlin Tian /
PubMed AbstractNeurokinin 3 receptor (NK3R) is a tachykinin receptor essential for the hypothalamic-pituitary-gonadal axis. The endogenous peptide agonist neurokinin B (NKB) preferentially activates NK3R, while ...Neurokinin 3 receptor (NK3R) is a tachykinin receptor essential for the hypothalamic-pituitary-gonadal axis. The endogenous peptide agonist neurokinin B (NKB) preferentially activates NK3R, while substance P (SP) binds preferentially to NK1R. In addition, the SP analogue senktide more potently activates NK3R than NKB and SP. However, the mechanisms of preferential binding of peptide and NK3R activation remain elusive. Herein, we determined the cryogenic electron microscopy (cryo-EM) structures of the NK3R-G complex bound to NKB, SP and senktide. The three NK3R-G/peptide complexes utilize a class of noncanonical receptor activation mechanisms. Combining the structural analysis and functional assay illustrated that the consensus C-termini of the three peptide agonists share a conserved binding mode to NK3R, while the divergent N-termini of the peptides confer the preferential binding of the agonist to NK3R. In addition, the specific interactions between the N-terminus of senktide and the N-terminus and extracellular loops (ECL2 and ECL3) of NK3R lead to the improved activation displayed by senktide compared to SP and NKB. These findings pave the way to understand tachykinin receptor subtype selectivity and provide ideas to rationally develop drugs targeting NK3R.
External linksCell Discov / PubMed:37391393 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 3.0 Å
Structure data

EMDB-36144, PDB-8jbf:
Senktide bound to active human neurokinin 3 receptor in complex with Gq
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-36145, PDB-8jbg:
Neurokinin B bound to active human neurokinin 3 receptor in complex with Gq
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-36146, PDB-8jbh:
Substance P bound to active human neurokinin 3 receptor in complex with Gq
Method: EM (single particle) / Resolution: 2.9 Å

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
  • mus musculoides (Temminck's mouse)
  • bos taurus (cattle)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / G protein coupled receptor / Neurokinin / Cryo-EM / Peptide Agonists

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