3MJ2

X-ray crystal structure of ITK complexed with inhibitor BMS-509744

Summary for 3MJ2

• Entry DOI: 10.2210/pdb3mj2/pdb
• Related: 3MIY 3MJ1
• Descriptor: Tyrosine-protein kinase ITK/TSK, N-[5-({5-[(4-acetylpiperazin-1-yl)carbonyl]-4-methoxy-2-methylphenyl}sulfanyl)-1,3-thiazol-2-yl]-4-({[(1S)-1,2,2-trimethylpropyl]amino}methyl)benzamide (3 entities in total)
• Functional Keywords: helix c-out, substrate blocking activation loop conformation, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane (By similarity): Q08881
• Total number of polymer chains: 1
• Total formula weight: 30740.25

Authors

Kuglstatter, A.,Villasenor, A.G. (deposition date: 2010-04-12, release date: 2010-06-30, Last modification date: 2023-09-06)

Primary citation

Kutach, A.K.,Villasenor, A.G.,Lam, D.,Belunis, C.,Janson, C.,Lok, S.,Hong, L.N.,Liu, C.M.,Deval, J.,Novak, T.J.,Barnett, J.W.,Chu, W.,Shaw, D.,Kuglstatter, A.
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, 2010

PubMed 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.

PubMed: 20545945
DOI: 10.1111/j.1747-0285.2010.00993.x

Experimental method

X-RAY DIFFRACTION (1.9 Å)