PDBsum entry 3mj2

Transferase

PDB id: 3mj2

Contents

Protein chain

259 a.a. *

Ligands

MJG

Waters ×167

* Residue conservation analysis

PDB id:

3mj2

Name:

Transferase

Title:

X-ray crystal structure of itk complexed with inhibitor bms-509744

Structure:

Tyrosine-protein kinase itk/tsk. Chain: a. Fragment: unp residues 357-620. Synonym: t-cell-specific kinase, tyrosine-protein kinase lyk, kinase emt. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: itk, emt, lyk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

1.90Å R-factor: 0.208 R-free: 0.252

Authors:

A.Kuglstatter,A.G.Villasenor

Key ref:

A.K.Kutach et al. (2010). Crystal structures of IL-2-inducible T cell kinase complexed with inhibitors: insights into rational drug design and activity regulation. Chem Biol Drug Des, 76, 154-163. PubMed id: 20545945

Date:

12-Apr-10 Release date: 30-Jun-10

Protein chain

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

Seq: 620 a.a.

Struc: 259 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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

Chem Biol Drug Des 76:154-163 (2010)

PubMed id: 20545945

Crystal structures of IL-2-inducible T cell kinase complexed with inhibitors: insights into rational drug design and activity regulation.

A.K.Kutach, A.G.Villaseñor, D.Lam, C.Belunis, C.Janson, S.Lok, L.N.Hong, C.M.Liu, J.Deval, T.J.Novak, J.W.Barnett, W.Chu, D.Shaw, A.Kuglstatter.

ABSTRACT

IL-2-inducible T cell kinase plays an essential role in T cell receptor signaling and is considered a drug target for the treatment of Th2-mediated inflammatory diseases. By applying high-throughput protein engineering and crystallization, we have determined the X-ray crystal structures of IL-2-inducible T cell kinase in complex with its selective inhibitor BMS-509744 and the broad-spectrum kinase inhibitors sunitinib and RO5191614. Sunitinib uniquely stabilizes IL-2-inducible T cell kinase in the helix C-in conformation by inducing side chain conformational changes in the ATP-binding site. This preference of sunitinib to bind to an active kinase conformation is reflective of its broad-spectrum kinase activity. BMS-509744 uniquely stabilizes the activation loop in a substrate-blocking inactive conformation, indicating that structural changes described for Src family kinases are also involved in the regulation of IL-2-inducible T cell kinase activity. The observed BMS-509744 binding mode allows rationalization of structure-activity relationships reported for this inhibitor class and facilitates further structure-based drug design. Sequence-based analysis of this binding mode provides guidance for the rational design of inhibitor selectivity.