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7D1C

Crystal structure of mouse Cryptochrome 1 in complex with compound TH303

Summary for 7D1C
Entry DOI10.2210/pdb7d1c/pdb
DescriptorCryptochrome-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)
Functional Keywordscryptochrome, cry, cry1, clock, circadian clock protein
Biological sourceMus musculus (Mouse)
Total number of polymer chains1
Total formula weight57859.26
Authors
Miller, S.A.,Hirota, T. (deposition date: 2020-09-14, release date: 2021-01-27, Last modification date: 2023-11-29)
Primary citationKolarski, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.91 Å)
Structure validation

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数据于2024-10-30公开中

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