PDBsum entry 1sm2

Transferase

PDB id: 1sm2

Contents

Protein chain

245 a.a. *

Ligands

STU ×2

Waters ×251

* Residue conservation analysis

PDB id:

1sm2

Name:

Transferase

Title:

Crystal structure of the phosphorylated interleukin-2 tyrosine kinase catalytic domain

Structure:

Tyrosine-protein kinase itk/tsk. Chain: a, b. Fragment: catalytic kinase domain. Synonym: t-cell-specific kinase, tyrosine-protein kinase lyk, kinase emt. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: itk, lyk, emt. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.30Å R-factor: 0.223 R-free: 0.292

Authors:

K.Brown,J.M.Long,S.C.M.Vial,N.Dedi,N.J.Dunster,S.B.Renwick, A.J.Tanner,J.D.Frantz,M.A.Fleming,G.M.T.Cheetham

Key ref:

K.Brown et al. (2004). Crystal structures of interleukin-2 tyrosine kinase and their implications for the design of selective inhibitors. J Biol Chem, 279, 18727-18732. PubMed id: 14766749 DOI: 10.1074/jbc.M400031200

Date:

08-Mar-04 Release date: 16-Jul-04

Protein chains

Q08881  (ITK_HUMAN) -  Tyrosine-protein kinase ITK/TSK from Homo sapiens

Seq: 620 a.a.

Struc: 245 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.M400031200

J Biol Chem 279:18727-18732 (2004)

PubMed id: 14766749

Crystal structures of interleukin-2 tyrosine kinase and their implications for the design of selective inhibitors.

K.Brown, J.M.Long, S.C.Vial, N.Dedi, N.J.Dunster, S.B.Renwick, A.J.Tanner, J.D.Frantz, M.A.Fleming, G.M.Cheetham.

ABSTRACT

Interleukin-2 tyrosine kinase, Itk, is an important member of the Tec family of non-receptor tyrosine kinases that play a central role in signaling through antigen receptors such as the T-cell receptor, B-cell receptor, and Fcepsilon. Selective inhibition of Itk may be an important way of modulating many diseases involving heightened or inappropriate activation of the immune system. In addition to an unliganded nonphophorylated Itk catalytic kinase domain, we determined the crystal structures of the phosphorylated and nonphosphorylated kinase domain bound to staurosporine, a potent broad-spectrum kinase inhibitor. These structures are useful for the design of novel, highly potent and selective Itk inhibitors and provide insight into the influence of inhibitor binding and phosphorylation on the conformation of Itk.

Selected figure(s)

Figure 2.
FIG. 2. Interactions between phosphorylated Itk (pTyr512) and staurosporine in the ATP-binding site. F[o] - F[c] experimental electron density for the inhibitor is shown in cyan, contoured at 1.5 and 2.3 Å resolution.

Figure 3.
FIG. 3. Conformational differences in the ATP-binding site of Btk (cyan ribbons and cyan side chains) and Itk (green ribbons and green side chains). Unphosphorylated and phosphorylated Itk adopts a closed catalytic conformation of the C-helix and glycine-rich loop. In contrast, the glycine-rich loop of unphosphorylated Btk blocks the ATP-binding site, which is not consistent with inhibitor binding. The Itk gatekeeper residue, Phe^435, and catalytically important residues are shown in detail. Itk residue numbering is used unless specified.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 18727-18732) copyright 2004.

Figures were selected by an automated process.