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PDBsum entry 3g0f
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References listed in PDB file
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Key reference
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Title
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Kit kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients.
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Authors
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K.S.Gajiwala,
J.C.Wu,
J.Christensen,
G.D.Deshmukh,
W.Diehl,
J.P.Dinitto,
J.M.English,
M.J.Greig,
Y.A.He,
S.L.Jacques,
E.A.Lunney,
M.Mctigue,
D.Molina,
T.Quenzer,
P.A.Wells,
X.Yu,
Y.Zhang,
A.Zou,
M.R.Emmett,
A.G.Marshall,
H.M.Zhang,
G.D.Demetri.
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Ref.
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Proc Natl Acad Sci U S A, 2009,
106,
1542-1547.
[DOI no: ]
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PubMed id
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Abstract
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Most gastrointestinal stromal tumors (GISTs) exhibit aberrant activation of the
receptor tyrosine kinase (RTK) KIT. The efficacy of the inhibitors imatinib
mesylate and sunitinib malate in GIST patients has been linked to their
inhibition of these mutant KIT proteins. However, patients on imatinib can
acquire secondary KIT mutations that render the protein insensitive to the
inhibitor. Sunitinib has shown efficacy against certain imatinib-resistant
mutants, although a subset that resides in the activation loop, including
D816H/V, remains resistant. Biochemical and structural studies were undertaken
to determine the molecular basis of sunitinib resistance. Our results show that
sunitinib targets the autoinhibited conformation of WT KIT and that the D816H
mutant undergoes a shift in conformational equilibrium toward the active state.
These findings provide a structural and enzymologic explanation for the
resistance profile observed with the KIT inhibitors. Prospectively, they have
implications for understanding oncogenic kinase mutants and for circumventing
drug resistance.
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Figure 1.
Overview of the KIT gene and protein. (A) Schematic
representation of KIT showing location of functional domains,
primary (1°) and secondary (2°) mutations (mut.).
Frequencies of primary KIT genotypes, specific secondary KIT
mutations, and resistance (R) or sensitivity (S) to imatinib
(IM) or sunitinib (SU) were those reported in a phase I/II trial
of sunitinib in advanced GIST after imatinib failure (6). V560D,
substitution of Asp for Val at residue 560. (B) The unactivated,
autoinhibited and activated forms of WT KIT (7, 8). The JM
domain (red), A-loop (green), and C α-helix (cyan) are oriented
differently in the autoinhibited and activated states. *V560D
generally occurs as a primary mutation.
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Figure 3.
Sunitinib recognizes the autoinhibited form of KIT. WT KIT
bound to sunitinib is shown in yellow (JM domain, red; A-loop,
green; C α-helix, cyan). (A) WT KIT bound to sunitinib is very
similar to the published autoinhibited structure of KIT (gray)
(7, 8). Amino acid side chains are shown at the sites of A-loop
substitutions found in sunitinib-resistant GISTs. (B)
Sunitinib-binding site in the complex and apo structures. Drug
binding induces a slight rearrangement of the Phe-811 side chain
relative to the apo form. (C) The overall structure of the D816H
mutant bound to sunitinib (darker blue) is very similar to that
with WT, except for the proposed dislocation of the JM domain
from its autoinhibitory position. Residue 816 is shown for both
proteins.
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