6KX7

Crystal structure of mouse Cryptochrome 1 in complex with TH301 compound

6KX7 の概要

• エントリーDOI: 10.2210/pdb6kx7/pdb
• 分子名称: Cryptochrome-1, 1-(4-chlorophenyl)-N-[2-(4-methoxyphenyl)-5,5-bis(oxidanylidene)-4,6-dihydrothieno[3,4-c]pyrazol-3-yl]cyclopentane-1-carboxamide (3 entities in total)
• 機能のキーワード: 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: 57857.72

構造登録者

Miller, S.A.,Aikawa, Y.,Hirota, T. (登録日: 2019-09-10, 公開日: 2020-04-01, 最終更新日: 2023-11-22)

主引用文献

Miller, S.,Son, Y.L.,Aikawa, Y.,Makino, E.,Nagai, Y.,Srivastava, A.,Oshima, T.,Sugiyama, A.,Hara, A.,Abe, K.,Hirata, K.,Oishi, S.,Hagihara, S.,Sato, A.,Tama, F.,Itami, K.,Kay, S.A.,Hatori, M.,Hirota, T.
Isoform-selective regulation of mammalian cryptochromes.
Nat.Chem.Biol., 16:676-685, 2020

PubMed Abstract: CRY1 and CRY2 are essential components of the circadian clock controlling daily physiological rhythms. Accumulating evidences indicate distinct roles of these highly homologous proteins, in addition to redundant functions. Therefore, the development of isoform-selective compounds represents an effective approach towards understanding the similarities and differences of CRY1 and CRY2 by controlling each isoform individually. We conducted phenotypic screenings of circadian clock modulators, and identified KL101 and TH301 that selectively stabilize CRY1 and CRY2, respectively. Crystal structures of CRY-compound complexes revealed conservation of compound-binding sites between CRY1 and CRY2. We further discovered a unique mechanism underlying compound selectivity in which the disordered C-terminal region outside the pocket was required for the differential effects of KL101 and TH301 against CRY isoforms. By using these compounds, we found a new role of CRY1 and CRY2 as enhancers of brown adipocyte differentiation, providing the basis of CRY-mediated regulation of energy expenditure.

PubMed: 32231341
DOI: 10.1038/s41589-020-0505-1

実験手法

X-RAY DIFFRACTION (2.1 Å)