Cryo–electron microscopy structures of human cone visual pigments.
Saved in:
| Title: | Cryo–electron microscopy structures of human cone visual pigments. |
|---|---|
| Authors: | Peng, Qi (AUTHOR), Li, Jian (AUTHOR), Jiang, Haihai (AUTHOR), Cheng, Xinyu (AUTHOR), Nag, Probal (AUTHOR), Kleinau, Gunnar (AUTHOR), Lamb, Trevor D. (AUTHOR), Busche, Leon (AUTHOR), Lu, Qiuyuan (AUTHOR), Zhou, Sili (AUTHOR), Liu, Yidi (AUTHOR), Zhang, Yuting (AUTHOR), Lv, Sijia (AUTHOR), Wan, Shuangyan (AUTHOR), Yang, Tingting (AUTHOR), Chen, Yixiang (AUTHOR), Zhang, Wei (AUTHOR), Nan, Weiwei (AUTHOR), Fu, Ying (AUTHOR), Che, Tong (AUTHOR) |
| Source: | Science. 6/25/2026, Vol. 392 Issue 6805, p1-12. 12p. |
| Subjects: | Visual pigments, Retinal (Visual pigment), Microscopy, Spectral sensitivity, Color vision, G protein coupled receptors |
| Abstract: | Human trichromatic color vision relies on three cone opsins [long-, middle-, and short-wavelength-sensitive opsins (LWS-, MWS-, and SWS-opsins, respectively)], whereas scotopic rod vision is mediated by rhodopsin. Although the structure of rhodopsin was solved more than 20 years ago, cone opsin structures have been lacking. Here, we present cryo–electron microscopy structures of the three human cone opsins, each bound to a G protein and all-trans retinal in the presumed active state. All three cone opsins differ markedly from rhodopsin. Within the retinal binding pocket, we identified a distinct counterion site (LWS- and MWS-opsins) and a ring of serines around the retinal (SWS-opsin). The active cone opsin structures explain how amino acid substitutions fine-tune spectral sensitivity and help clarify the molecular basis of color vision deficiencies and key differences in rod versus cone activation. 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: Human trichromatic color vision relies on cone photopigments containing long-, middle-, and short-wavelength-sensitive opsins (LWS-, MWS-, and SWS-opsins, respectively). By contrast, vision at very-low light intensities depends on the rod photopigment, rhodopsin. All of these photopigments share a common vitamin A–derived chromophore, 11-cis retinal, which binds covalently to each opsin via a Schiff base linkage, forming photopigments with characteristic absorption maxima at ~420 nm (SWS-opsin), 530 nm (MWS-opsin), 560 nm (LWS-opsin), and 500 nm (rhodopsin). Upon light absorption, retinal isomerizes to its agonistic all-trans conformation, triggering the protein into an active state that enables coupling to a G protein, thereby initiating the signaling cascade. The active structures of all three human cone opsins are reported here. RATIONALE: To elucidate the structures of human LWS-, MWS-, and SWS-opsins in their active states, each opsin was complexed with a heterotrimeric Gi protein and exposed to the agonist all-trans retinal. Cryo–electron microscopy (cryo-EM) structures of these complexes were determined, with overall resolutions of 3.35 Å for the LWS-opsin–Gi complex, 2.48 Å for MWS-opsin–Gi, and 2.61 Å for SWS-opsin–Gi. RESULTS: The cryo-EM structures of the active-state cone opsin–Gi complexes reveal distinct molecular features. Whereas all three cone opsins share a conserved seven-transmembrane helix (TM1 to TM7) architecture similar to that of rhodopsin, the LWS- and MWS-opsins likely use E1022.53 (Glu at position 1022.53)from TM2 as the counterion of the Schiff base in the active state. This differs from both rhodopsin, which uses E181ECL2 in extracellular loop 2 (ECL2) as its active-state counterion, and SWS-opsin, which we found uses E178ECL2 in this role. Structural analysis shows that SWS-opsin possesses a polar serine-rich environment around the Schiff base, which contributes to stabilization of the active state and may partly account for the blue shift in the spectral absorbance of SWS-opsin. In addition, SWS-opsin contains an extra disulfide bond between TM2 and TM7, which creates a structural constraint and an expanded water cavity near the Schiff base—features not observed in other visual opsins. These findings provide structural insights for distinct electrostatic stabilization mechanisms among cone opsins, which are critical for spectral tuning, as well as for the stability and decay of the active state. Multiscale simulations validate the retinal environments observed in the cryo-EM structures of active cone opsins and link them to spectroscopic results. CONCLUSION: The cryo-EM structures identify key structural determinants of cone opsin stability and function and provide detailed insights into their mode of action. They provide a basis for future studies on the function and dynamics of cone opsins and offer a framework for understanding the molecular mechanisms underlying rod and cone phototransduction, as well as initial insights into the structural basis of many cone disorders. Cryo-EM structures of human cone visual pigments.: Human trichromatic (photopic) color vision is mediated by three cone photoreceptors (L-, M-, and S-cones) concentrated in the central foveal region of the retina, whereas rhodopsin-expressing rod photoreceptors outside the fovea mediate vision under dim light (scotopic). Cryo-EM structures of the active states of the three cone opsin proteins responsible for color vision (LWS-, MWS-, and SWS-opsins) in complex with the heterotrimeric Gi protein and all-trans retinal reveal distinct molecular features. Structural findings suggest different active-state counterion and toggle-switch sites in LWS- and MWS-opsins (E102 and W281) compared with SWS-opsin (E178 and Y262). SWS-opsin exhibits a pronounced polar, serine-rich environment (a "serine ring") surrounding the retinal Schiff base, which partially explains its spectral blue shift. E, Glu; H, His; K, Lys; L, Leu; Q, Gln; S, Ser; W, Trp; Y, Tyr. [Figure partly created with BioRender.com and PyMol] [ABSTRACT FROM AUTHOR] |
| Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
|
Full text is not displayed to guests.
Login for full access.
|
|
| Abstract: | Human trichromatic color vision relies on three cone opsins [long-, middle-, and short-wavelength-sensitive opsins (LWS-, MWS-, and SWS-opsins, respectively)], whereas scotopic rod vision is mediated by rhodopsin. Although the structure of rhodopsin was solved more than 20 years ago, cone opsin structures have been lacking. Here, we present cryo–electron microscopy structures of the three human cone opsins, each bound to a G protein and all-trans retinal in the presumed active state. All three cone opsins differ markedly from rhodopsin. Within the retinal binding pocket, we identified a distinct counterion site (LWS- and MWS-opsins) and a ring of serines around the retinal (SWS-opsin). The active cone opsin structures explain how amino acid substitutions fine-tune spectral sensitivity and help clarify the molecular basis of color vision deficiencies and key differences in rod versus cone activation. 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: Human trichromatic color vision relies on cone photopigments containing long-, middle-, and short-wavelength-sensitive opsins (LWS-, MWS-, and SWS-opsins, respectively). By contrast, vision at very-low light intensities depends on the rod photopigment, rhodopsin. All of these photopigments share a common vitamin A–derived chromophore, 11-cis retinal, which binds covalently to each opsin via a Schiff base linkage, forming photopigments with characteristic absorption maxima at ~420 nm (SWS-opsin), 530 nm (MWS-opsin), 560 nm (LWS-opsin), and 500 nm (rhodopsin). Upon light absorption, retinal isomerizes to its agonistic all-trans conformation, triggering the protein into an active state that enables coupling to a G protein, thereby initiating the signaling cascade. The active structures of all three human cone opsins are reported here. RATIONALE: To elucidate the structures of human LWS-, MWS-, and SWS-opsins in their active states, each opsin was complexed with a heterotrimeric Gi protein and exposed to the agonist all-trans retinal. Cryo–electron microscopy (cryo-EM) structures of these complexes were determined, with overall resolutions of 3.35 Å for the LWS-opsin–Gi complex, 2.48 Å for MWS-opsin–Gi, and 2.61 Å for SWS-opsin–Gi. RESULTS: The cryo-EM structures of the active-state cone opsin–Gi complexes reveal distinct molecular features. Whereas all three cone opsins share a conserved seven-transmembrane helix (TM1 to TM7) architecture similar to that of rhodopsin, the LWS- and MWS-opsins likely use E1022.53 (Glu at position 1022.53)from TM2 as the counterion of the Schiff base in the active state. This differs from both rhodopsin, which uses E181ECL2 in extracellular loop 2 (ECL2) as its active-state counterion, and SWS-opsin, which we found uses E178ECL2 in this role. Structural analysis shows that SWS-opsin possesses a polar serine-rich environment around the Schiff base, which contributes to stabilization of the active state and may partly account for the blue shift in the spectral absorbance of SWS-opsin. In addition, SWS-opsin contains an extra disulfide bond between TM2 and TM7, which creates a structural constraint and an expanded water cavity near the Schiff base—features not observed in other visual opsins. These findings provide structural insights for distinct electrostatic stabilization mechanisms among cone opsins, which are critical for spectral tuning, as well as for the stability and decay of the active state. Multiscale simulations validate the retinal environments observed in the cryo-EM structures of active cone opsins and link them to spectroscopic results. CONCLUSION: The cryo-EM structures identify key structural determinants of cone opsin stability and function and provide detailed insights into their mode of action. They provide a basis for future studies on the function and dynamics of cone opsins and offer a framework for understanding the molecular mechanisms underlying rod and cone phototransduction, as well as initial insights into the structural basis of many cone disorders. Cryo-EM structures of human cone visual pigments.: Human trichromatic (photopic) color vision is mediated by three cone photoreceptors (L-, M-, and S-cones) concentrated in the central foveal region of the retina, whereas rhodopsin-expressing rod photoreceptors outside the fovea mediate vision under dim light (scotopic). Cryo-EM structures of the active states of the three cone opsin proteins responsible for color vision (LWS-, MWS-, and SWS-opsins) in complex with the heterotrimeric Gi protein and all-trans retinal reveal distinct molecular features. Structural findings suggest different active-state counterion and toggle-switch sites in LWS- and MWS-opsins (E102 and W281) compared with SWS-opsin (E178 and Y262). SWS-opsin exhibits a pronounced polar, serine-rich environment (a "serine ring") surrounding the retinal Schiff base, which partially explains its spectral blue shift. E, Glu; H, His; K, Lys; L, Leu; Q, Gln; S, Ser; W, Trp; Y, Tyr. [Figure partly created with BioRender.com and PyMol] [ABSTRACT FROM AUTHOR] |
|---|---|
| ISSN: | 00368075 |
| DOI: | 10.1126/science.adz8141 |
