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1000
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Abstract/Summary
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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–Gq complex bound to NKB, SP and senktide. The
three NK3R–Gq/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.
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