6TW2

Re-refined crystal structure of di-phosphorylated human CLK1 in complex with a novel substituted indole inhibitor

6TW2 の概要

• エントリーDOI: 10.2210/pdb6tw2/pdb
• 分子名称: Dual specificity protein kinase CLK1, ethyl 3-[(E)-2-amino-1-cyanoethenyl]-6,7-dichloro-1-methyl-1H-indole-2-carboxylate (3 entities in total)
• 機能のキーワード: serine/threonine-protein kinase, tyrosine-protein kinase, nucleus, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40079.66

構造登録者

Loll, B.,Haltenhof, T.,Heyd, F.,Wahl, M.C. (登録日: 2020-01-12, 公開日: 2020-02-05, 最終更新日: 2024-10-09)

主引用文献

Haltenhof, T.,Kotte, A.,De Bortoli, F.,Schiefer, S.,Meinke, S.,Emmerichs, A.K.,Petermann, K.K.,Timmermann, B.,Imhof, P.,Franz, A.,Loll, B.,Wahl, M.C.,Preussner, M.,Heyd, F.
A Conserved Kinase-Based Body-Temperature Sensor Globally Controls Alternative Splicing and Gene Expression.
Mol.Cell, 78:57-69.e4, 2020

PubMed Abstract: Homeothermic organisms maintain their core body temperature in a narrow, tightly controlled range. Whether and how subtle circadian oscillations or disease-associated changes in core body temperature are sensed and integrated in gene expression programs remain elusive. Furthermore, a thermo-sensor capable of sensing the small temperature differentials leading to temperature-dependent sex determination (TSD) in poikilothermic reptiles has not been identified. Here, we show that the activity of CDC-like kinases (CLKs) is highly responsive to physiological temperature changes, which is conferred by structural rearrangements within the kinase activation segment. Lower body temperature activates CLKs resulting in strongly increased phosphorylation of SR proteins in vitro and in vivo. This globally controls temperature-dependent alternative splicing and gene expression, with wide implications in circadian, tissue-specific, and disease-associated settings. This temperature sensor is conserved across evolution and adapted to growth temperatures of diverse poikilotherms. The dynamic temperature range of reptilian CLK homologs suggests a role in TSD.

PubMed: 32059760
DOI: 10.1016/j.molcel.2020.01.028

実験手法

X-RAY DIFFRACTION (1.8 Å)