Research ArticleBiochemistry

Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1

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Science Signaling  25 Sep 2018:
Vol. 11, Issue 549, eaau0597
DOI: 10.1126/scisignal.aau0597

Targeting pseudokinases with kinase inhibitors

Pseudokinases are structurally similar to kinases but lack catalytic activity; instead, pseudokinases typically function as scaffolds, often promoting the degradation of substrate proteins by bringing them into close proximity with ubiquitin ligases. Two studies explored the structures and protein interactions of the pseudokinases TRIB1 (Jamieson et al.) and TRIB2 (Foulkes et al.). Their findings reveal new insights into the structural regulation of TRIB proteins and show that these proteins, which are implicated in leukemia and other cancers, can bind to clinically approved kinase inhibitors. Binding by these drugs caused structural changes in the TRIB proteins that deprotected them from degradation upon interacting with ubiquitin ligases, indicating that these drugs might be repurposed to block the function of TRIBs in cancer patients.

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