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PDBsum entry 3mj2
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References listed in PDB file
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Key reference
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Title
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Crystal structures of il-2-Inducible t cell kinase complexed with inhibitors: insights into rational drug design and activity regulation.
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Authors
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A.K.Kutach,
A.G.Villaseñor,
D.Lam,
C.Belunis,
C.Janson,
S.Lok,
L.N.Hong,
C.M.Liu,
J.Deval,
T.J.Novak,
J.W.Barnett,
W.Chu,
D.Shaw,
A.Kuglstatter.
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Ref.
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Chem Biol Drug Des, 2010,
76,
154-163.
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PubMed id
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Abstract
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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.
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