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- Title
Crystal Structures of IL-2-inducible T cell Kinase Complexed with Inhibitors: Insights into Rational Drug Design and Activity Regulation.
- Authors
Kutach, Alan K.; Villaseñor, Armando G.; Lam, Diana; Belunis, Charles; Janson, Cheryl; Lok, Stephen; Li-Na Hong; Chao-Min Liu; Deval, Jerome; Novak, Thomas J.; Barnett, Jim W.; Wei Chu; Shaw, David; Kuglstatter, Andreas
- 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.
- Subjects
DRUG design; DOSAGE forms of drugs; T cells; SPECTRUM analysis; DRUG delivery systems
- Publication
Chemical Biology & Drug Design, 2010, Vol 76, Issue 2, p154
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/j.1747-0285.2010.00993.x