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Structural insights into spectral tuning and retinal exchange in cone visual pigments.

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Title:	Structural insights into spectral tuning and retinal exchange in cone visual pigments.
Authors:	Ohashi, Sayaka (AUTHOR), Katayama, Kota (AUTHOR), Kojima, Asato (AUTHOR), Yang, Xuchun (AUTHOR), Fukuda, Masahiro (AUTHOR), Sacchetta, Filippo (AUTHOR), Suno, Ryoji (AUTHOR), Sugita, Yukihiko (AUTHOR), Nuemket, Nipawan (AUTHOR), Kim, Suhyang (AUTHOR), Kobayashi, Kazuhiro (AUTHOR), Imai, Hiroo (AUTHOR), Iwata, So (AUTHOR), Nango, Eriko (AUTHOR), Kobayashi, Takuya (AUTHOR), Noda, Takeshi (AUTHOR), Olivucci, Massimo (AUTHOR), Kato, Hideaki E. (AUTHOR), Kandori, Hideki (AUTHOR)
Source:	Science. 6/25/2026, Vol. 392 Issue 6805, p1-15. 15p.
Abstract:	Color vision in catarrhine primates relies on red-, green-, and blue-sensitive cone pigments that share an 11-cis-retinal chromophore but differ in absorption maxima. Red and green pigments arose by recent gene duplication and differ at only a few residues. Here, we report cryo–electron microscopy structures of red and green cone pigments from the cynomolgus macaque (Macaca fascicularis) integrated with low-temperature vibrational spectroscopy and quantum mechanical and molecular mechanical modeling. The red-green spectral shift is dominated by threonine 285, the hydroxyl dipole of which modulates chromophore electrostatics, whereas steric effects appear modest. We also identified membrane-facing lateral openings in cone pigments but not in inactive rhodopsin. Comparisons with active-state structures suggest activation-dependent gating, and mutational and spectroscopic analyses support a role for this opening in retinal uptake and rapid pigment regeneration. Editor's summary: Human daytime vision relies on a trio of visual receptors called opsins, which are found in the cone cells in and around the central region of the retina. The three opsins are tuned to long, medium, or short wavelengths of light, roughly corresponding to red, green, and blue, and mutations or other defects in cone cell function can lead to vision deficits. Although the cell biology and biochemistry of color vision have been well studied, up to now, the molecular explanation for cone opsin spectral tuning and signaling kinetics has been limited by a lack of experimental structures. Three papers in this issue now resolve this deficit. Schmidt et al. determined structures of the dark state of the green and blue human cone opsins, which revealed important details of these receptors and provide a basis for a femtosecond-resolution spectroscopy study. Ohashi et al. performed complementary structural, spectroscopic, and computational results with dark-state red and green cone opsins from macaques, which have color vision similar to humans. Finally, Peng et al. studied all three human cone opsins in the presumed active state bound to a G protein and all-trans retinal. The three papers together provide a clear picture of the features of these visual receptors that lead to different spectral properties, activation and inactivation kinetics, and recycling. —Michael A. Funk INTRODUCTION: Color vision allows primates to distinguish objects based on subtle differences in light wavelength. In humans and Old World primates, this ability depends on three types of cone cells, red, green, and blue, each using a light-sensitive pigment that is most sensitive to a different part of the visible spectrum. The red- and green-sensitive pigments are particularly intriguing: They differ at only a few amino acid positions, yet their light absorption peaks are separated by about 30 nanometers, enabling red-green color discrimination. Cone pigments also differ from the rod pigment rhodopsin, having faster activation and much more rapid regeneration after light exposure. Explaining this combination of precise spectral tuning and rapid retinal exchange has been difficult without direct structural information. RATIONALE: Understanding how small sequence differences give rise to large functional changes of cone pigments requires direct structural information. Although high-resolution structures of rhodopsin have long been available, cone pigments have been difficult to study because of their instability and experimental challenges. To overcome these limitations, we focused on red and green cone pigments from the cynomolgus macaque (Macaca fascicularis), a primate species with a visual system that closely resembles that of humans. By combining cryo–electron microscopy with vibrational spectroscopy and quantum chemical modeling, we aimed to clarify how cone pigments tune their spectral sensitivity, how they exchange their retinal chromophore, and how their activation mechanisms compare with those of rhodopsin. RESULTS: We elucidated inactive-state structures of primate red and green cone pigments, revealing that red-green spectral tuning is driven by a small number of amino acid substitutions. The largest effect comes from placing a threonine residue with a hydroxyl group near the retinal chromophore, which shifts spectral sensitivity mainly by altering the local electrostatic environment rather than by forcing the retinal backbone into a markedly different shape. Additional substitutions, including sites located farther from the chromophore, make smaller, additive contributions. By contrast, several differences between cone pigments and rhodopsin reflect broader changes in chromophore geometry and electrostatic organization. We also uncovered a previously unrecognized membrane-facing opening in cone pigments that is absent in inactive rhodopsin. Mutational experiments and structural comparisons suggest that this opening facilitates rapid uptake of retinal, providing a structural explanation for the fast regeneration required for cone function in bright light. Structural comparisons between inactive cone pigment structures presented in this study and previously reported active states further show that cone pigments share core activation mechanisms with rhodopsin but have a less-rigid network stabilizing the inactive state, which may contribute to their faster response kinetics. CONCLUSION: These findings connect long-standing functional differences in color vision to concrete structural features. Small sequence changes tune color by reshaping the electrostatic field acting on the retinal chromophore, whereas distinct membrane-access pathways enable efficient chromophore exchange and rapid recovery. More broadly, this work illustrates general principles by which G protein–coupled receptors diversify their function through subtle structural adaptations, offering broadly relevant insights into how receptor proteins evolve specialized functions from a shared molecular framework. Structural basis of spectral tuning and rapid recycling in cone pigments.: Structures of catarrhine primate green and red cone pigments reveal how subtle amino acid changes tune color sensitivity through electrostatic effects near retinal, and a cone-specific membrane-facing opening (pore 2) enables rapid chromophore regeneration. Together with activation-dependent gating, this opening provides a structural portal for efficient retinal uptake and fast cone pigment regeneration. [ABSTRACT FROM AUTHOR]
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Database:	Psychology and Behavioral Sciences Collection

Description
Abstract:	Color vision in catarrhine primates relies on red-, green-, and blue-sensitive cone pigments that share an 11-cis-retinal chromophore but differ in absorption maxima. Red and green pigments arose by recent gene duplication and differ at only a few residues. Here, we report cryo–electron microscopy structures of red and green cone pigments from the cynomolgus macaque (Macaca fascicularis) integrated with low-temperature vibrational spectroscopy and quantum mechanical and molecular mechanical modeling. The red-green spectral shift is dominated by threonine 285, the hydroxyl dipole of which modulates chromophore electrostatics, whereas steric effects appear modest. We also identified membrane-facing lateral openings in cone pigments but not in inactive rhodopsin. Comparisons with active-state structures suggest activation-dependent gating, and mutational and spectroscopic analyses support a role for this opening in retinal uptake and rapid pigment regeneration. Editor's summary: Human daytime vision relies on a trio of visual receptors called opsins, which are found in the cone cells in and around the central region of the retina. The three opsins are tuned to long, medium, or short wavelengths of light, roughly corresponding to red, green, and blue, and mutations or other defects in cone cell function can lead to vision deficits. Although the cell biology and biochemistry of color vision have been well studied, up to now, the molecular explanation for cone opsin spectral tuning and signaling kinetics has been limited by a lack of experimental structures. Three papers in this issue now resolve this deficit. Schmidt et al. determined structures of the dark state of the green and blue human cone opsins, which revealed important details of these receptors and provide a basis for a femtosecond-resolution spectroscopy study. Ohashi et al. performed complementary structural, spectroscopic, and computational results with dark-state red and green cone opsins from macaques, which have color vision similar to humans. Finally, Peng et al. studied all three human cone opsins in the presumed active state bound to a G protein and all-trans retinal. The three papers together provide a clear picture of the features of these visual receptors that lead to different spectral properties, activation and inactivation kinetics, and recycling. —Michael A. Funk INTRODUCTION: Color vision allows primates to distinguish objects based on subtle differences in light wavelength. In humans and Old World primates, this ability depends on three types of cone cells, red, green, and blue, each using a light-sensitive pigment that is most sensitive to a different part of the visible spectrum. The red- and green-sensitive pigments are particularly intriguing: They differ at only a few amino acid positions, yet their light absorption peaks are separated by about 30 nanometers, enabling red-green color discrimination. Cone pigments also differ from the rod pigment rhodopsin, having faster activation and much more rapid regeneration after light exposure. Explaining this combination of precise spectral tuning and rapid retinal exchange has been difficult without direct structural information. RATIONALE: Understanding how small sequence differences give rise to large functional changes of cone pigments requires direct structural information. Although high-resolution structures of rhodopsin have long been available, cone pigments have been difficult to study because of their instability and experimental challenges. To overcome these limitations, we focused on red and green cone pigments from the cynomolgus macaque (Macaca fascicularis), a primate species with a visual system that closely resembles that of humans. By combining cryo–electron microscopy with vibrational spectroscopy and quantum chemical modeling, we aimed to clarify how cone pigments tune their spectral sensitivity, how they exchange their retinal chromophore, and how their activation mechanisms compare with those of rhodopsin. RESULTS: We elucidated inactive-state structures of primate red and green cone pigments, revealing that red-green spectral tuning is driven by a small number of amino acid substitutions. The largest effect comes from placing a threonine residue with a hydroxyl group near the retinal chromophore, which shifts spectral sensitivity mainly by altering the local electrostatic environment rather than by forcing the retinal backbone into a markedly different shape. Additional substitutions, including sites located farther from the chromophore, make smaller, additive contributions. By contrast, several differences between cone pigments and rhodopsin reflect broader changes in chromophore geometry and electrostatic organization. We also uncovered a previously unrecognized membrane-facing opening in cone pigments that is absent in inactive rhodopsin. Mutational experiments and structural comparisons suggest that this opening facilitates rapid uptake of retinal, providing a structural explanation for the fast regeneration required for cone function in bright light. Structural comparisons between inactive cone pigment structures presented in this study and previously reported active states further show that cone pigments share core activation mechanisms with rhodopsin but have a less-rigid network stabilizing the inactive state, which may contribute to their faster response kinetics. CONCLUSION: These findings connect long-standing functional differences in color vision to concrete structural features. Small sequence changes tune color by reshaping the electrostatic field acting on the retinal chromophore, whereas distinct membrane-access pathways enable efficient chromophore exchange and rapid recovery. More broadly, this work illustrates general principles by which G protein–coupled receptors diversify their function through subtle structural adaptations, offering broadly relevant insights into how receptor proteins evolve specialized functions from a shared molecular framework. Structural basis of spectral tuning and rapid recycling in cone pigments.: Structures of catarrhine primate green and red cone pigments reveal how subtle amino acid changes tune color sensitivity through electrostatic effects near retinal, and a cone-specific membrane-facing opening (pore 2) enables rapid chromophore regeneration. Together with activation-dependent gating, this opening provides a structural portal for efficient retinal uptake and fast cone pigment regeneration. [ABSTRACT FROM AUTHOR]
ISSN:	00368075
DOI:	10.1126/science.adz3996