2nry: Difference between revisions

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==Overview==

Interleukin-1 (IL-1) receptor-associated kinase-4 (IRAK-4) is a, serine/threonine kinase that plays an essential role in signal, transduction by Toll/IL-1 receptors (TIRs). Here, we report the crystal, structures of the phosphorylated human IRAK-4 kinase domain in complex, with a potent inhibitor and with staurosporine to 2.0 and 2.2 A, respectively. The structures reveal that IRAK-4 has a unique tyrosine, gatekeeper residue that interacts with the conserved glutamate from helix, alphaC. Consequently, helix alphaC is "pulled in" to maintain the active, orientation, and the usual pre-existing hydrophobic back pocket of the, ATP-binding site is abolished. The peptide substrate-binding site is more, open when compared with other protein kinases due to a marked movement of, helix alphaG. The pattern of phosphate ligand interactions in the, activation loop bears a close resemblance to that of a tyrosine kinase., Our results provide insights into IRAK-4 function and the design of, selective inhibitors.

Interleukin-1 (IL-1) receptor-associated kinase-4 (IRAK-4) is a serine/threonine kinase that plays an essential role in signal transduction by Toll/IL-1 receptors (TIRs). Here, we report the crystal structures of the phosphorylated human IRAK-4 kinase domain in complex with a potent inhibitor and with staurosporine to 2.0 and 2.2 A, respectively. The structures reveal that IRAK-4 has a unique tyrosine gatekeeper residue that interacts with the conserved glutamate from helix alphaC. Consequently, helix alphaC is "pulled in" to maintain the active orientation, and the usual pre-existing hydrophobic back pocket of the ATP-binding site is abolished. The peptide substrate-binding site is more open when compared with other protein kinases due to a marked movement of helix alphaG. The pattern of phosphate ligand interactions in the activation loop bears a close resemblance to that of a tyrosine kinase. Our results provide insights into IRAK-4 function and the design of selective inhibitors.

==Disease==

Known diseases associated with this structure: IRAK4 deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606883 606883]], Invasive pneumococcal disease, recurrent isolated, 1 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606883 606883]]

==About this Structure==

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[[Category: Single protein]]

[[Category: Liu, J.]]

[[Category: Walker, N.P.C.]]

[[Category: Walker, N P.C.]]

[[Category: Wang, Z.]]

[[Category: STU]]

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[[Category: staurosporine]]

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@@ Line 4: / Line 4: @@
 ==Overview==
-Interleukin-1 (IL-1) receptor-associated kinase-4 (IRAK-4) is a, serine/threonine kinase that plays an essential role in signal, transduction by Toll/IL-1 receptors (TIRs). Here, we report the crystal, structures of the phosphorylated human IRAK-4 kinase domain in complex, with a potent inhibitor and with staurosporine to 2.0 and 2.2 A, respectively. The structures reveal that IRAK-4 has a unique tyrosine, gatekeeper residue that interacts with the conserved glutamate from helix, alphaC. Consequently, helix alphaC is "pulled in" to maintain the active, orientation, and the usual pre-existing hydrophobic back pocket of the, ATP-binding site is abolished. The peptide substrate-binding site is more, open when compared with other protein kinases due to a marked movement of, helix alphaG. The pattern of phosphate ligand interactions in the, activation loop bears a close resemblance to that of a tyrosine kinase., Our results provide insights into IRAK-4 function and the design of, selective inhibitors.
+Interleukin-1 (IL-1) receptor-associated kinase-4 (IRAK-4) is a serine/threonine kinase that plays an essential role in signal transduction by Toll/IL-1 receptors (TIRs). Here, we report the crystal structures of the phosphorylated human IRAK-4 kinase domain in complex with a potent inhibitor and with staurosporine to 2.0 and 2.2 A, respectively. The structures reveal that IRAK-4 has a unique tyrosine gatekeeper residue that interacts with the conserved glutamate from helix alphaC. Consequently, helix alphaC is "pulled in" to maintain the active orientation, and the usual pre-existing hydrophobic back pocket of the ATP-binding site is abolished. The peptide substrate-binding site is more open when compared with other protein kinases due to a marked movement of helix alphaG. The pattern of phosphate ligand interactions in the activation loop bears a close resemblance to that of a tyrosine kinase. Our results provide insights into IRAK-4 function and the design of selective inhibitors.
+==Disease==
+Known diseases associated with this structure: IRAK4 deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606883 606883]], Invasive pneumococcal disease, recurrent isolated, 1 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606883 606883]]
 ==About this Structure==
@@ Line 15: / Line 18: @@
 [[Category: Single protein]]
 [[Category: Liu, J.]]
-[[Category: Walker, N.P.C.]]
+[[Category: Walker, N P.C.]]
 [[Category: Wang, Z.]]
 [[Category: STU]]
@@ Line 22: / Line 25: @@
 [[Category: staurosporine]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:24:26 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:10:15 2008''