PDBsum entry 4hcu

Transferase/transferase inhibitor

PDB id: 4hcu

Contents

Protein chain

263 a.a.

Ligands

13L

Waters ×224

PDB id:

4hcu

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of itk in complext with compound 40

Structure:

Tyrosine-protein kinase itk/tsk. Chain: a. Fragment: unp residues 354-620. Synonym: interleukin-2-inducible t-cell kinase, il-2-inducible t-cell kinase, kinase emt, t-cell-specific kinase, tyrosine-protein kinase lyk. Engineered: yes. Mutation: yes

Source:

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

Resolution:

1.43Å R-factor: 0.170 R-free: 0.191

Authors:

S.Han,N.Caspers

Key ref:

C.W.Zapf et al. (2012). Covalent inhibitors of interleukin-2 inducible T cell kinase (itk) with nanomolar potency in a whole-blood assay. J Med Chem, 55, 10047-10063. PubMed id: 23098091

Date:

01-Oct-12 Release date: 14-Nov-12

Protein chain

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

Seq: 620 a.a.

Struc: 263 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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

J Med Chem 55:10047-10063 (2012)

PubMed id: 23098091

Covalent inhibitors of interleukin-2 inducible T cell kinase (itk) with nanomolar potency in a whole-blood assay.

C.W.Zapf, B.S.Gerstenberger, L.Xing, D.C.Limburg, D.R.Anderson, N.Caspers, S.Han, A.Aulabaugh, R.Kurumbail, S.Shakya, X.Li, V.Spaulding, R.M.Czerwinski, N.Seth, Q.G.Medley.

ABSTRACT

We wish to report a strategy that targets interleukin-2inducible T cell kinase (Itk) with covalent inhibitors. Thus far, covalent inhibition of Itk has not been disclosed in the literature. Structure-based drug design was utilized to achieve low nanomolar potency of the disclosed series even at high ATP concentrations. Kinetic measurements confirmed an irreversible binding mode with off-rate half-lives exceeding 24 h and moderate on-rates. The analogues are highly potent in a cellular IP1 assay as well as in a human whole-blood (hWB) assay. Despite a half-life of approximately 2 h in resting primary T cells, the covalent inhibition of Itk resulted in functional silencing of the TCR pathway for more than 24 h. This prolonged effect indicates that covalent inhibition is a viable strategy to target the inactivation of Itk.