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PDBsum entry 1rjb
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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The structural basis for autoinhibition of flt3 by the juxtamembrane domain.
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Authors
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J.Griffith,
J.Black,
C.Faerman,
L.Swenson,
M.Wynn,
F.Lu,
J.Lippke,
K.Saxena.
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Ref.
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Mol Cell, 2004,
13,
169-178.
[DOI no: ]
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PubMed id
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Abstract
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FLT3 is a type III receptor tyrosine kinase that is thought to play a key role
in hematopoiesis. Certain classes of FLT3 mutations cause constitutively
activated forms of the receptor that are found in significant numbers of
patients with acute myelogenous leukemia (AML). The mutations occur either in
the activation loop, for example, as point mutations of Asp835 or as internal
tandem duplication (ITD) sequences in the juxtamembrane (JM) domain. To further
understand the nature of FLT3 autoinhibition and regulation, we have determined
the crystal structure of the autoinhibited form of FLT3. This structure shows
the autoinhibitory conformation of a complete JM domain in this class of
receptor tyrosine kinases. The detailed inhibitory mechanism of the JM domain is
revealed, which is likely utilized by other members of type III receptor
tyrosine kinases.
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Figure 4.
Figure 4. Active Site of FLT3Closeup view of the active
site region of FLT3 showing the relationship of Tyr572 and
Tyr842 hydrogen bonded to Glu661 and Asp811, respectively, which
in turn are involved in salt bridges.
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Figure 5.
Figure 5. Activation Loops Can Adopt a Wide Range of
ConformationsThe superposition of the closed activation loop
from FLT3 onto (A) the closed IRK-I activation loop (blue), (B)
the partially open FGFR activation loop (red), and (C) the fully
open IRK-A activation loop (blue).
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2004,
13,
169-178)
copyright 2004.
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