1byg

From Proteopedia

(Difference between revisions)

Revision as of 10:09, 25 December 2014

KINASE DOMAIN OF HUMAN C-TERMINAL SRC KINASE (CSK) IN COMPLEX WITH INHIBITOR STAUROSPORINE

Structural highlights

1byg is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:	Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2
Resources:	FirstGlance, OCA, RCSB, PDBsum

Function

[CSK_HUMAN] Non-receptor tyrosine-protein kinase that plays an important role in the regulation of cell growth, differentiation, migration and immune response. Phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, FYN, LYN or YES1. Upon tail phosphorylation, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane. Suppresses signaling by various surface receptors, including T-cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and maintaining inactive several positive effectors such as FYN or LCK.^[1] ^[2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The crystal structure of the kinase domain of C-terminal Src kinase (CSK) has been determined by molecular replacement, co-complexed with the protein kinase inhibitor staurosporine (crystals belong to the space group P21212 with a=44.5 A, b=120.6 A, c=48.3 A). The final model of CSK has been refined to an R-factor of 19.9 % (Rfree=28.7 %) at 2.4 A resolution. The structure consists of a small, N-terminal lobe made up mostly of a beta-sheet, and a larger C-terminal lobe made up mostly of alpha-helices. The structure reveals atomic details of interactions with staurosporine, which binds in a deep cleft between the lobes. The polypeptide chain fold of CSK is most similar to c-Src, Hck and fibroblast growth factor receptor 1 kinase (FGFR1K) and most dissimilar to insulin receptor kinase (IRK). Interactions between the N and C-terminal lobe are mediated by the bound staurosporine molecule and by hydrogen bonds. In addition, there are several water molecules forming lobe-bridging hydrogen bonds, which may be important for maintaining the catalytic integrity of the kinase. Furthermore, the conserved Lys328 and Glu267 residues utilise water in the formation of a molecular pivot which is essential in allowing relative movement of the N and C-terminal lobes. An analysis of the residues around the ATP-binding site reveals structural differences with other protein tyrosine kinases. Most notable of these are different orientations of the conserved residues Asp332 and Phe333, suggesting that inhibitor binding proceeds via an induced fit. These structural observations have implications for understanding protein tyrosine kinase catalytic mechanisms and for the design of ATP-mimicking inhibitors of protein kinases.

Structure of the protein tyrosine kinase domain of C-terminal Src kinase (CSK) in complex with staurosporine.,Lamers MB, Antson AA, Hubbard RE, Scott RK, Williams DH J Mol Biol. 1999 Jan 15;285(2):713-25. PMID:9878439^[3]

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

References

↑ Bergman M, Mustelin T, Oetken C, Partanen J, Flint NA, Amrein KE, Autero M, Burn P, Alitalo K. The human p50csk tyrosine kinase phosphorylates p56lck at Tyr-505 and down regulates its catalytic activity. EMBO J. 1992 Aug;11(8):2919-24. PMID:1639064
↑ Sun G, Budde RJ. Expression, purification, and initial characterization of human Yes protein tyrosine kinase from a bacterial expression system. Arch Biochem Biophys. 1997 Sep 1;345(1):135-42. PMID:9281320 doi:10.1006/abbi.1997.0236
↑ Lamers MB, Antson AA, Hubbard RE, Scott RK, Williams DH. Structure of the protein tyrosine kinase domain of C-terminal Src kinase (CSK) in complex with staurosporine. J Mol Biol. 1999 Jan 15;285(2):713-25. PMID:9878439 doi:10.1006/jmbi.1998.2369

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1byg"

@@ Line 7: / Line 7: @@
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1byg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1byg OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1byg RCSB], [http://www.ebi.ac.uk/pdbsum/1byg PDBsum]</span></td></tr>
 </table>
+== Function ==
+[[http://www.uniprot.org/uniprot/CSK_HUMAN CSK_HUMAN]] Non-receptor tyrosine-protein kinase that plays an important role in the regulation of cell growth, differentiation, migration and immune response. Phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, FYN, LYN or YES1. Upon tail phosphorylation, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane. Suppresses signaling by various surface receptors, including T-cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and maintaining inactive several positive effectors such as FYN or LCK.<ref>PMID:1639064</ref> <ref>PMID:9281320</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]

1byg

From Proteopedia

Revision as of 10:09, 25 December 2014

KINASE DOMAIN OF HUMAN C-TERMINAL SRC KINASE (CSK) IN COMPLEX WITH INHIBITOR STAUROSPORINE

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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