PDBsum entry 4qd6

Transferase/transferase inhibitor

PDB id: 4qd6

Contents

Protein chains

244 a.a.

Ligands

30T ×2

Waters ×19

PDB id:

4qd6

Name:

Transferase/transferase inhibitor

Title:

Itk kinase domain in complex with inhibitor compound

Structure:

Tyrosine-protein kinase itk/tsk. Chain: a, b. Fragment: unp residues 357-620. 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:

2.45Å R-factor: 0.212 R-free: 0.267

Authors:

P.A.Mcewan,J.J.Barker,C.Eigenbrot

Key ref:

G.Trani et al. (2014). Design, synthesis and structure-activity relationships of a novel class of sulfonylpyridine inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Bioorg Med Chem Lett, 24, 5818-5823. PubMed id: 25455497 DOI: 10.1016/j.bmcl.2014.10.020

Date:

13-May-14 Release date: 14-Jan-15

Protein chains

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

Seq: 620 a.a.

Struc: 244 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

DOI no: 10.1016/j.bmcl.2014.10.020

Bioorg Med Chem Lett 24:5818-5823 (2014)

PubMed id: 25455497

Design, synthesis and structure-activity relationships of a novel class of sulfonylpyridine inhibitors of Interleukin-2 inducible T-cell kinase (ITK).

G.Trani, J.J.Barker, S.M.Bromidge, F.A.Brookfield, J.D.Burch, Y.Chen, C.Eigenbrot, A.Heifetz, M.H.Ismaili, A.Johnson, T.M.Krülle, C.H.MacKinnon, R.Maghames, P.A.McEwan, C.A.Montalbetti, D.F.Ortwine, Y.Pérez-Fuertes, D.G.Vaidya, X.Wang, A.A.Zarrin, Z.Pei.

ABSTRACT

Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.