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Photopharmacological Manipulation of Mammalian CRY1 for Regulation of the Circadian Clock
[Image: see text] CRY1 and CRY2 proteins are highly conserved components of the circadian clock that controls daily physiological rhythms. Disruption of CRY functions are related to many diseases, including circadian sleep phase disorder. Development of isoform-selective and spatiotemporally control...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863067/ https://www.ncbi.nlm.nih.gov/pubmed/33464888 http://dx.doi.org/10.1021/jacs.0c12280 |
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author | Kolarski, Dušan Miller, Simon Oshima, Tsuyoshi Nagai, Yoshiko Aoki, Yugo Kobauri, Piermichele Srivastava, Ashutosh Sugiyama, Akiko Amaike, Kazuma Sato, Ayato Tama, Florence Szymanski, Wiktor Feringa, Ben L. Itami, Kenichiro Hirota, Tsuyoshi |
author_facet | Kolarski, Dušan Miller, Simon Oshima, Tsuyoshi Nagai, Yoshiko Aoki, Yugo Kobauri, Piermichele Srivastava, Ashutosh Sugiyama, Akiko Amaike, Kazuma Sato, Ayato Tama, Florence Szymanski, Wiktor Feringa, Ben L. Itami, Kenichiro Hirota, Tsuyoshi |
author_sort | Kolarski, Dušan |
collection | PubMed |
description | [Image: see text] CRY1 and CRY2 proteins are highly conserved components of the circadian clock that controls daily physiological rhythms. Disruption of CRY functions are related to many diseases, including circadian sleep phase disorder. Development of isoform-selective and spatiotemporally controllable tools will facilitate the understanding of shared and distinct functions of CRY1 and CRY2. Here, we developed CRY1-selective compounds that enable light-dependent manipulation of the circadian clock. From phenotypic chemical screening in human cells, we identified benzophenone derivatives that lengthened the circadian period. These compounds selectively interacted with the CRY1 photolyase homology region, resulting in activation of CRY1 but not CRY2. The benzophenone moiety rearranged a CRY1 region called the “lid loop” located outside of the compound-binding pocket and formed a unique interaction with Phe409 in the lid loop. Manipulation of this key interaction was achieved by rationally designed replacement of the benzophenone with a switchable azobenzene moiety whose cis–trans isomerization can be controlled by light. The metastable cis form exhibited sufficiently high half-life in aqueous solutions and structurally mimicked the benzophenone unit, enabling reversible period regulation over days by cellular irradiation with visible light. This study revealed an unprecedented role of the lid loop in CRY-compound interaction and paves the way for spatiotemporal regulation of CRY1 activity by photopharmacology for molecular understanding of CRY1-dependent functions in health and disease. |
format | Online Article Text |
id | pubmed-7863067 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-78630672021-02-05 Photopharmacological Manipulation of Mammalian CRY1 for Regulation of the Circadian Clock Kolarski, Dušan Miller, Simon Oshima, Tsuyoshi Nagai, Yoshiko Aoki, Yugo Kobauri, Piermichele Srivastava, Ashutosh Sugiyama, Akiko Amaike, Kazuma Sato, Ayato Tama, Florence Szymanski, Wiktor Feringa, Ben L. Itami, Kenichiro Hirota, Tsuyoshi J Am Chem Soc [Image: see text] CRY1 and CRY2 proteins are highly conserved components of the circadian clock that controls daily physiological rhythms. Disruption of CRY functions are related to many diseases, including circadian sleep phase disorder. Development of isoform-selective and spatiotemporally controllable tools will facilitate the understanding of shared and distinct functions of CRY1 and CRY2. Here, we developed CRY1-selective compounds that enable light-dependent manipulation of the circadian clock. From phenotypic chemical screening in human cells, we identified benzophenone derivatives that lengthened the circadian period. These compounds selectively interacted with the CRY1 photolyase homology region, resulting in activation of CRY1 but not CRY2. The benzophenone moiety rearranged a CRY1 region called the “lid loop” located outside of the compound-binding pocket and formed a unique interaction with Phe409 in the lid loop. Manipulation of this key interaction was achieved by rationally designed replacement of the benzophenone with a switchable azobenzene moiety whose cis–trans isomerization can be controlled by light. The metastable cis form exhibited sufficiently high half-life in aqueous solutions and structurally mimicked the benzophenone unit, enabling reversible period regulation over days by cellular irradiation with visible light. This study revealed an unprecedented role of the lid loop in CRY-compound interaction and paves the way for spatiotemporal regulation of CRY1 activity by photopharmacology for molecular understanding of CRY1-dependent functions in health and disease. American Chemical Society 2021-01-19 2021-02-03 /pmc/articles/PMC7863067/ /pubmed/33464888 http://dx.doi.org/10.1021/jacs.0c12280 Text en © 2021 American Chemical Society This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License (http://pubs.acs.org/page/policy/authorchoice_ccbyncnd_termsofuse.html) , which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes. |
spellingShingle | Kolarski, Dušan Miller, Simon Oshima, Tsuyoshi Nagai, Yoshiko Aoki, Yugo Kobauri, Piermichele Srivastava, Ashutosh Sugiyama, Akiko Amaike, Kazuma Sato, Ayato Tama, Florence Szymanski, Wiktor Feringa, Ben L. Itami, Kenichiro Hirota, Tsuyoshi Photopharmacological Manipulation of Mammalian CRY1 for Regulation of the Circadian Clock |
title | Photopharmacological
Manipulation of Mammalian CRY1
for Regulation of the Circadian Clock |
title_full | Photopharmacological
Manipulation of Mammalian CRY1
for Regulation of the Circadian Clock |
title_fullStr | Photopharmacological
Manipulation of Mammalian CRY1
for Regulation of the Circadian Clock |
title_full_unstemmed | Photopharmacological
Manipulation of Mammalian CRY1
for Regulation of the Circadian Clock |
title_short | Photopharmacological
Manipulation of Mammalian CRY1
for Regulation of the Circadian Clock |
title_sort | photopharmacological
manipulation of mammalian cry1
for regulation of the circadian clock |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863067/ https://www.ncbi.nlm.nih.gov/pubmed/33464888 http://dx.doi.org/10.1021/jacs.0c12280 |
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