6TW2
Re-refined crystal structure of di-phosphorylated human CLK1 in complex with a novel substituted indole inhibitor
Summary for 6TW2
| Entry DOI | 10.2210/pdb6tw2/pdb |
| Descriptor | 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) |
| Functional Keywords | serine/threonine-protein kinase, tyrosine-protein kinase, nucleus, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 40079.66 |
| Authors | Loll, B.,Haltenhof, T.,Heyd, F.,Wahl, M.C. (deposition date: 2020-01-12, release date: 2020-02-05, Last modification date: 2024-10-09) |
| Primary citation | 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 Cited by 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: 32059760DOI: 10.1016/j.molcel.2020.01.028 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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