The @entity71414 ( @entity71414 ) pseudokinase binds to XXXX and autophosphorylates in a metal-independent manner.

@entity1 @entity3534 @entity18410 @entity33378 @entity5 @entity71414 @entity376 @entity460 @entity4334 @entity11064 @entity855
The @entity1 Tribbles (TRB)-related pseudokinases are CAMK ( @entity460 /calmodulin-dependent protein kinase)-related family members that have evolved a series of highly unusual motifs in the 'pseudocatalytic' domain. In canonical kinases, conserved @entity3534 bind to divalent metal ions and align @entity855 prior to efficient @entity11064 -transfer to substrates. However, in pseudokinases, atypical residues give rise to diverse and often unstudied biochemical and structural features that are thought to be central to cellular functions. TRB proteins play a crucial role in multiple signalling networks and overexpression confers @entity5 phenotypes on @entity1 cells, marking TRB pseudokinases out as a novel class of drug target. In the present paper, we report that the @entity1 pseudokinase @entity71414 retains the ability to both bind and hydrolyse @entity855 weakly in  vitro. Kinase activity is metal-independent and involves a catalytic @entity376 residue, which is conserved in TRB proteins throughout evolution alongside several unique @entity3534 in the active site. A similar low level of autophosphorylation is also preserved in the closely related @entity1 @entity18410 . By employing chemical genetics, we establish that the @entity4334 -binding site of an 'analogue-sensitive' (AS) @entity71414 mutant can be targeted with specific bulky ligands of the @entity33378 (PP) chemotype. Our analysis confirms that @entity71414 retains low levels of @entity855 binding and/or catalysis that is targetable with small molecules. Given the significant clinical successes associated with targeting of @entity5 -associated kinases with small molecule inhibitors, it is likely that similar approaches will be useful for further evaluating the TRB pseudokinases, with the translation of this information likely to furnish new leads for drug discovery.
