7D1C

Crystal structure of mouse Cryptochrome 1 in complex with compound TH303

7D1C の概要

• エントリーDOI: 10.2210/pdb7d1c/pdb
• 分子名称: Cryptochrome-1, N-[2-(4-methoxyphenyl)-5,5-bis(oxidanylidene)-4,6-dihydrothieno[3,4-c]pyrazol-3-yl]-4-(phenylcarbonyl)benzamide (3 entities in total)
• 機能のキーワード: cryptochrome, cry, cry1, clock, circadian clock protein
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 57859.26

構造登録者

Miller, S.A.,Hirota, T. (登録日: 2020-09-14, 公開日: 2021-01-27, 最終更新日: 2023-11-29)

主引用文献

Kolarski, D.,Miller, S.,Oshima, T.,Nagai, Y.,Aoki, Y.,Kobauri, P.,Srivastava, A.,Sugiyama, A.,Amaike, K.,Sato, A.,Tama, F.,Szymanski, W.,Feringa, B.L.,Itami, K.,Hirota, T.
Photopharmacological Manipulation of Mammalian CRY1 for Regulation of the Circadian Clock.
J.Am.Chem.Soc., 143:2078-2087, 2021

PubMed Abstract: 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 isomerization can be controlled by light. The metastable 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.

PubMed: 33464888
DOI: 10.1021/jacs.0c12280

実験手法

X-RAY DIFFRACTION (1.91 Å)