6ruu

From Proteopedia

Pseudokinase domain of human IRAK3

PDB ID 6ruu

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Structural highlights

6ruu is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.95Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

IRAK3_HUMAN Disease susceptibility is associated with variations affecting the gene represented in this entry.

Function

IRAK3_HUMAN Inhibits dissociation of IRAK1 and IRAK4 from the Toll-like receptor signaling complex by either inhibiting the phosphorylation of IRAK1 and IRAK4 or stabilizing the receptor complex.[UniProtKB:Q8K4B2]^[1]

Publication Abstract from PubMed

Interleukin-1 receptor associated kinases (IRAKs) are key players in innate immune signaling that mediate the host response to pathogens. In contrast to the active kinases IRAK1 and IRAK4, IRAK2 and IRAK3 are pseudokinases lacking catalytic activity and their functions are poorly understood. IRAK3 is thought to be a negative regulator of innate immune signaling and mutations in IRAK3 are associated with asthma and cancer. Here, we report the crystal structure of the human IRAK3 pseudokinase domain in a closed, pseudoactive conformation. IRAK3 dimerizes in a unique way through a head-to-head arrangement not observed in any other kinases. Multiple conserved cysteine residues imply a potential redox control of IRAK3 conformation and dimerization. By analyzing asthma-associated mutations, we identify an evolutionarily conserved surface on IRAK3 that could form an interaction interface with IRAK4, suggesting a model for the negative regulation of IRAK4 by IRAK3.

Dimeric Structure of the Pseudokinase IRAK3 Suggests an Allosteric Mechanism for Negative Regulation.,Lange SM, Nelen MI, Cohen P, Kulathu Y Structure. 2020 Nov 17. pii: S0969-2126(20)30416-0. doi:, 10.1016/j.str.2020.11.004. PMID:33238146^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z. IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family. J Biol Chem. 1999 Jul 2;274(27):19403-10. PMID:10383454
↑ Lange SM, Nelen MI, Cohen P, Kulathu Y. Dimeric Structure of the Pseudokinase IRAK3 Suggests an Allosteric Mechanism for Negative Regulation. Structure. 2020 Nov 17. pii: S0969-2126(20)30416-0. doi:, 10.1016/j.str.2020.11.004. PMID:33238146 doi:http://dx.doi.org/10.1016/j.str.2020.11.004