Molecular basis underlying the specificity of an antagonist AA92593 for mammalian melanopsins DOI Creative Commons

Kohei Obayashi,

Runming Zou, Takashi Kawaguchi

и другие.

Journal of Biological Chemistry, Год журнала: 2025, Номер unknown, С. 108461 - 108461

Опубликована: Март 1, 2025

Melanopsin functions in intrinsically photosensitive retinal ganglion cells of mammals to regulate circadian clock and pupil constriction. The opsinamide AA92593 has been reported specifically inhibit mouse human melanopsin as a competitive antagonist against retinal; however, the molecular mechanisms underlying its specificity have not resolved. In this study, we attempted identify amino acid residues responsible for susceptibility mammalian melanopsins AA92593. Our cell-based assays confirmed that effectively inhibited light-induced cellular responses melanopsins, but those non-mammalian vertebrate invertebrate melanopsins. These results suggest conserved among are important antagonistic effect AA92593, noticed Phe-942.61, Ser-188ECL2, Ser-2696.52 candidate residues. Substitutions these reduced We conducted docking dynamics simulations based on AlphaFold-predicted structure. indicated located at AA92593-binding site, additionally identified Trp-189ECL2 Leu-2075.42 interacting with antagonist. affected Furthermore, substitutions converted AA92593-insensitive susceptible Based experiments simulations, five residues, positions 942.61, 188ECL2, 189ECL2, 2075.42, 2696.52, were found be specific

Язык: Английский

Molecular basis underlying the specificity of an antagonist AA92593 for mammalian melanopsins DOI Creative Commons

Kohei Obayashi,

Runming Zou, Takashi Kawaguchi

и другие.

Journal of Biological Chemistry, Год журнала: 2025, Номер unknown, С. 108461 - 108461

Опубликована: Март 1, 2025

Melanopsin functions in intrinsically photosensitive retinal ganglion cells of mammals to regulate circadian clock and pupil constriction. The opsinamide AA92593 has been reported specifically inhibit mouse human melanopsin as a competitive antagonist against retinal; however, the molecular mechanisms underlying its specificity have not resolved. In this study, we attempted identify amino acid residues responsible for susceptibility mammalian melanopsins AA92593. Our cell-based assays confirmed that effectively inhibited light-induced cellular responses melanopsins, but those non-mammalian vertebrate invertebrate melanopsins. These results suggest conserved among are important antagonistic effect AA92593, noticed Phe-942.61, Ser-188ECL2, Ser-2696.52 candidate residues. Substitutions these reduced We conducted docking dynamics simulations based on AlphaFold-predicted structure. indicated located at AA92593-binding site, additionally identified Trp-189ECL2 Leu-2075.42 interacting with antagonist. affected Furthermore, substitutions converted AA92593-insensitive susceptible Based experiments simulations, five residues, positions 942.61, 188ECL2, 189ECL2, 2075.42, 2696.52, were found be specific

Язык: Английский

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