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PDBsum entry 2p0c
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References listed in PDB file
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Key reference
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Title
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Structural insights into the inhibited states of the mer receptor tyrosine kinase.
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Authors
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X.Huang,
P.Finerty,
J.R.Walker,
C.Butler-Cole,
M.Vedadi,
M.Schapira,
S.A.Parker,
B.E.Turk,
D.A.Thompson,
S.Dhe-Paganon.
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Ref.
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J Struct Biol, 2009,
165,
88-96.
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PubMed id
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Abstract
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The mammalian ortholog of the retroviral oncogene v-Eyk, and a receptor tyrosine
kinase upstream of antiapoptotic and transforming signals, Mer (MerTK) is a
mediator of the phagocytic process, being involved in retinal and immune cell
clearance and platelet aggregation. Mer knockout mice are viable and are
protected from epinephrine-induced pulmonary thromboembolism and ferric
chloride-induced thrombosis. Mer overexpression, on the other hand, is
associated with numerous carcinomas. Although Mer adaptor proteins and signaling
pathways have been identified, it remains unclear how Mer initiates
phagocytosis. When bound to its nucleotide cofactor, the high-resolution
structure of Mer shows an autoinhibited alphaC-Glu-out conformation with
insertion of an activation loop residue into the active site. Mer complexed with
compound-52 (C52:
2-(2-hydroxyethylamino)-6-(3-chloroanilino)-9-isopropylpurine), a ligand
identified from a focused library, retains its DFG-Asp-in and alphaC-Glu-out
conformation, but acquires other conformational changes. The alphaC helix and
DFGL region is closer to the hinge region and the ethanolamine moiety of C52
binds in the groove formed between Leu593 and Val601 of the P-loop, causing a
compression of the active site pocket. These conformational states reveal the
mechanisms of autoinhibition, the pathophysiological basis of disease-causing
mutations, and a platform for the development of chemical probes.
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Secondary reference #1
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Title
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Cloning and mRNA expression analysis of a novel human protooncogene, C-Mer.
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Authors
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D.K.Graham,
T.L.Dawson,
D.L.Mullaney,
H.R.Snodgrass,
H.S.Earp.
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Ref.
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Cell Growth Differ, 1994,
5,
647-657.
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PubMed id
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Secondary reference #2
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Title
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Erratum
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Authors
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D.K.Graham,
T.L.Dawson,
D.L.Mullaney,
H.R.Snodgrass,
H.S.Earp.
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Ref.
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Cell Growth Differ, 1994,
5,
1022-1022.
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Secondary reference #3
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Title
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Mutations in mertk, The human orthologue of the rcs rat retinal dystrophy gene, Cause retinitis pigmentosa.
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Authors
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A.Gal,
Y.Li,
D.A.Thompson,
J.Weir,
U.Orth,
S.G.Jacobson,
E.Apfelstedt-Sylla,
D.Vollrath.
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Ref.
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Nat Genet, 2000,
26,
270-271.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1. MERTK structure and mutations. a, The 19 coding
exons of human MERTK (GenBank AF260514−529) are depicted,
along with segments encoding various functional domains of the
protein: immunoglobulin-like (Ig-like), fibronectin-like
(FN-like), transmembrane (TM) and tyrosine kinase (TK). Vertical
arrows show the locations of identified mutations. Dashed lines
indicate that exons 1 and 19 include untranslated sequences that
are not depicted. b, Electropherograms demonstrating mutant
(top) and normal (bottom) sequences. An arrow indicates the
intron 10/exon 11 boundary.
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The above figure is
reproduced from the cited reference
with permission from Macmillan Publishers Ltd
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