IRAK4 Structure and Function

The first crystal structure of IRAK4 was published in 2006 and, at the time of writing this review, 19 structures have been deposited into the RCSB protein data bank including 14 structures exhibiting a bound inhibitor [25]. IRAK4 has an indicative kinase fold comprised of N-terminal and C-terminal lobes, with the active site residing between the two (Fig. 2). One unique feature of the IRAK family is that all members contain a tyrosine gatekeeper, which does not exist in any other human kinases. The large gatekeeper, and the interaction of the phenol of Tyr262 with E233 on the a-C helix, prevents access to the back hydrophobic pocket utilized by type II kinase inhibitors. Other features of the IRAK4-binding site

Crystal structure of IRAK catalytic domain with bound staurosporine

Fig. 2 Crystal structure of IRAK catalytic domain with bound staurosporine.

include a hinge region consisting of Val263, Tyr264, and Met265; as well as, the catalytic lysine 213, which is ubiquitous to all catalytically active kinases. The cocrystal structure in Fig. 2 highlights the binding mode of staurosporine to IRAK4, where two H-bonds are made to the hinge. Another feature, typical of many of the inhibitors described in this review, is a n—n interaction with the Tyr262 gatekeeper and the western aromatic ring of staurosporine. The furan ring of staurosporine binds in the ribose pocket, which is where the ribose unit of ATP binds in during substrate phosphorylation.

The two catalytically active members of the IRAK family (IRAK1 and IRAK4) have 31% overall sequence identity; however, when looking at the region surrounding the ATP-binding site, the two are highly homologous with a 93% sequence similarity (5 A from staurosporine). One difference between the two proteins is the presence of Met192 in IRAK4. This sits over the top of the ATP-binding site, while in IRAK1 it is an isoleucine residue. Another major difference is the composition of the amino acid sequence in the hinge region. Valine (Val263), tyrosine (Tyr264), and methionine (Met265) are found in IRAK4, while glycine, phenylalanine, and leucine are observed in IRAKI. Even though the sequence similarity is high between IRAK4 and IRAKI, our experience with three different series ofIRAK4 inhibitors is that selectivity for IRAK4 over IRAK1 is easily achieved (unpublished data). Interestingly, we are not aware of any compounds that are selective for IRAK1 over IRAK4, which could be due to the lack of effort towards selective IRAK1 inhibition.

 
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