PDBsum entry 1xbb

Transferase

PDB id: 1xbb

Contents

Protein chain

268 a.a. *

Ligands

STI

Waters ×357

* Residue conservation analysis

PDB id:

1xbb

Name:

Transferase

Title:

Crystal structure of the syk tyrosine kinase domain with gleevec

Structure:

Tyrosine-protein kinase syk. Chain: a. Synonym: spleen tyrosine kinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: syk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

1.57Å R-factor: 0.191 R-free: 0.221

Authors:

V.L.Nienaber,S.Atwell,J.M.Adams,J.Badger,M.D.Buchanan,I.K.Feil, K.J.Froning,X.Gao,J.Hendle,K.Keegan,B.C.Leon,H.J.Muller-Deickmann, B.W.Noland,K.Post,K.R.Rajashankar,A.Ramos,M.Russell,S.K.Burley, S.G.Buchanan

Key ref:

S.Atwell et al. (2004). A novel mode of Gleevec binding is revealed by the structure of spleen tyrosine kinase. J Biol Chem, 279, 55827-55832. PubMed id: 15507431 DOI: 10.1074/jbc.M409792200

Date:

30-Aug-04 Release date: 02-Nov-04

Protein chain

P43405  (KSYK_HUMAN) -  Tyrosine-protein kinase SYK from Homo sapiens

Seq: 635 a.a.

Struc: 268 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1074/jbc.M409792200

J Biol Chem 279:55827-55832 (2004)

PubMed id: 15507431

A novel mode of Gleevec binding is revealed by the structure of spleen tyrosine kinase.

S.Atwell, J.M.Adams, J.Badger, M.D.Buchanan, I.K.Feil, K.J.Froning, X.Gao, J.Hendle, K.Keegan, B.C.Leon, H.J.Müller-Dieckmann, V.L.Nienaber, B.W.Noland, K.Post, K.R.Rajashankar, A.Ramos, M.Russell, S.K.Burley, S.G.Buchanan.

ABSTRACT

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.

Selected figure(s)

Figure 2.
FIG. 2. Stereo view of alternate Gleevec binding modes. Gleevec bound to unphosphorylated Abl (green) adopts an extended, trans-confirmation, which is incompatible with the phosphorylated/more active confirmation of Abl (blue). Gleevec binds to the unphosphorylated/active confirmation of Syk (yellow) in a very different cis-conformation, which is more compatible with binding to the phosphorylated/more active conformation of Abl (blue). The key residues are labeled.

Figure 4.
FIG. 4. A, binding of Gleevec to Syk. Ligand difference electron density (2 F[observed]-F[calculated]) contoured at 1 . B, binding of Gleevec and staurosporine to Syk. Gleevec (yellow) binding to Syk in the compact cis-conformation mimics the structure and binding mode of staurosporine (salmon). The key residues are labeled, and hydrogen bonds are denoted with dashed lines. The images were prepared with Xfit (25).

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 55827-55832) copyright 2004.

Figures were selected by the author.