1xba: Difference between revisions

Revision as of 16:53, 21 February 2008

Crystal structure of apo syk tyrosine kinase domain

OverviewOverview

Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase required for signaling from immunoreceptors in various hematopoietic cells. Phosphorylation of two tyrosine residues in the activation loop of the Syk kinase catalytic domain is necessary for signaling, a phenomenon typical of tyrosine kinase family members. Syk in vitro enzyme activity, however, does not depend on phosphorylation (activation loop tyrosine --> phenylalanine mutants retain catalytic activity). We have determined the x-ray structure of the unphosphorylated form of the kinase catalytic domain of Syk. The enzyme adopts a conformation of the activation loop typically seen only in activated, phosphorylated tyrosine kinases, explaining why Syk does not require phosphorylation for activation. We also demonstrate that Gleevec (STI-571, Imatinib) inhibits the isolated kinase domains of both unphosphorylated Syk and phosphorylated Abl with comparable potency. Gleevec binds Syk in a novel, compact cis-conformation that differs dramatically from the binding mode observed with unphosphorylated Abl, the more Gleevec-sensitive form of Abl. This finding suggests the existence of two distinct Gleevec binding modes: an extended, trans-conformation characteristic of tight binding to the inactive conformation of a protein kinase and a second compact, cis-conformation characteristic of weaker binding to the active conformation. Finally, the Syk-bound cis-conformation of Gleevec bears a striking resemblance to the rigid structure of the nonspecific, natural product kinase inhibitor staurosporine.

About this StructureAbout this Structure

1XBA is a Single protein structure of sequence from Homo sapiens. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.

ReferenceReference

A novel mode of Gleevec binding is revealed by the structure of spleen tyrosine kinase., Atwell S, Adams JM, Badger J, Buchanan MD, Feil IK, Froning KJ, Gao X, Hendle J, Keegan K, Leon BC, Muller-Dieckmann HJ, Nienaber VL, Noland BW, Post K, Rajashankar KR, Ramos A, Russell M, Burley SK, Buchanan SG, J Biol Chem. 2004 Dec 31;279(53):55827-32. Epub 2004 Oct 26. PMID:15507431

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OCA

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-[[Image:1xba.gif|left|200px]]<br />
+[[Image:1xba.gif|left|200px]]<br /><applet load="1xba" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1xba" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1xba, resolution 2.00&Aring;" />
 '''Crystal structure of apo syk tyrosine kinase domain'''<br />
 ==Overview==
-Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase required, for signaling from immunoreceptors in various hematopoietic cells., Phosphorylation of two tyrosine residues in the activation loop of the Syk, kinase catalytic domain is necessary for signaling, a phenomenon typical, of tyrosine kinase family members. Syk in vitro enzyme activity, however, does not depend on phosphorylation (activation loop tyrosine --&gt;, phenylalanine mutants retain catalytic activity). We have determined the, x-ray structure of the unphosphorylated form of the kinase catalytic, domain of Syk. The enzyme adopts a conformation of the activation loop, typically seen only in activated, phosphorylated tyrosine kinases, explaining why Syk does not require phosphorylation for activation. We, also demonstrate that Gleevec (STI-571, Imatinib) inhibits the isolated, kinase domains of both unphosphorylated Syk and phosphorylated Abl with, comparable potency. Gleevec binds Syk in a novel, compact cis-conformation, that differs dramatically from the binding mode observed with, unphosphorylated Abl, the more Gleevec-sensitive form of Abl. This finding, suggests the existence of two distinct Gleevec binding modes: an extended, trans-conformation characteristic of tight binding to the inactive, conformation of a protein kinase and a second compact, cis-conformation, characteristic of weaker binding to the active conformation. Finally, the, Syk-bound cis-conformation of Gleevec bears a striking resemblance to the, rigid structure of the nonspecific, natural product kinase inhibitor, staurosporine.
+Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase required for signaling from immunoreceptors in various hematopoietic cells. Phosphorylation of two tyrosine residues in the activation loop of the Syk kinase catalytic domain is necessary for signaling, a phenomenon typical of tyrosine kinase family members. Syk in vitro enzyme activity, however, does not depend on phosphorylation (activation loop tyrosine --&gt; phenylalanine mutants retain catalytic activity). We have determined the x-ray structure of the unphosphorylated form of the kinase catalytic domain of Syk. The enzyme adopts a conformation of the activation loop typically seen only in activated, phosphorylated tyrosine kinases, explaining why Syk does not require phosphorylation for activation. We also demonstrate that Gleevec (STI-571, Imatinib) inhibits the isolated kinase domains of both unphosphorylated Syk and phosphorylated Abl with comparable potency. Gleevec binds Syk in a novel, compact cis-conformation that differs dramatically from the binding mode observed with unphosphorylated Abl, the more Gleevec-sensitive form of Abl. This finding suggests the existence of two distinct Gleevec binding modes: an extended, trans-conformation characteristic of tight binding to the inactive conformation of a protein kinase and a second compact, cis-conformation characteristic of weaker binding to the active conformation. Finally, the Syk-bound cis-conformation of Gleevec bears a striking resemblance to the rigid structure of the nonspecific, natural product kinase inhibitor staurosporine.
 ==About this Structure==
-XBA is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1XBA OCA].
+XBA is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XBA OCA].
 ==Reference==
@@ Line 15: / Line 14: @@
 [[Category: Single protein]]
 [[Category: Transferase]]
-[[Category: Adams, J.M.]]
+[[Category: Adams, J M.]]
 [[Category: Atwell, S.]]
 [[Category: Badger, J.]]
-[[Category: Buchanan, M.D.]]
+[[Category: Buchanan, M D.]]
-[[Category: Buchanan, S.G.]]
+[[Category: Buchanan, S G.]]
-[[Category: Burley, S.K.]]
+[[Category: Burley, S K.]]
-[[Category: Feil, I.K.]]
+[[Category: Feil, I K.]]
-[[Category: Froning, K.J.]]
+[[Category: Froning, K J.]]
 [[Category: Gao, X.]]
 [[Category: Hendle, J.]]
 [[Category: Keegan, K.]]
-[[Category: Leon, B.C.]]
+[[Category: Leon, B C.]]
-[[Category: Muller-Deickmann, H.J.]]
+[[Category: Muller-Deickmann, H J.]]
-[[Category: Nienaber, V.L.]]
+[[Category: Nienaber, V L.]]
-[[Category: Noland, B.W.]]
+[[Category: Noland, B W.]]
 [[Category: Post, K.]]
-[[Category: Rajashankar, K.R.]]
+[[Category: Rajashankar, K R.]]
 [[Category: Ramos, A.]]
 [[Category: Russell, M.]]
@@ Line 39: / Line 38: @@
 [[Category: structural genomix]]
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