title: Crystal structures of IL-2-inducible T cell kinase complexed with inhibitors: insights into rational drug design and activity regulation.
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.
authors.affiliation: Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Kutach
authors.forename: Armando G
authors.initials: AG
authors.lastname: Villaseñor
authors.forename: Diana
authors.initials: D
authors.lastname: Lam
authors.forename: Charles
authors.initials: C
authors.lastname: Belunis
authors.forename: Cheryl
authors.initials: C
authors.lastname: Janson
authors.forename: Stephen
authors.initials: S
authors.lastname: Lok
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Hong
authors.forename: Chao-Min
authors.initials: CM
authors.lastname: Liu
authors.forename: Jerome
authors.initials: J
authors.lastname: Deval
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Novak
authors.forename: Jim W
authors.initials: JW
authors.lastname: Barnett
authors.forename: Wei
authors.initials: W
authors.lastname: Chu
authors.forename: David
authors.initials: D
authors.lastname: Shaw
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D015202:Protein Engineering; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000077210:Sunitinib; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; D019061:src-Family Kinases; D000077210:Sunitinib