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PDBsum entry 4mha
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Transferase/transferase inhibitor
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PDB id
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4mha
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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase mer in complex with inhibitor unc1817
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Structure:
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Tyrosine-protein kinase mer. Chain: a, b. Fragment: catalytic domain, unp residues 570-864. Synonym: proto-oncogenE C-mer, receptor tyrosine kinase mertk. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: mer, mertk. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.59Å
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R-factor:
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0.247
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R-free:
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0.294
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Authors:
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W.Zhang,A.Mciver,M.A.Stashko,D.Deryckere,B.R.Branchford,D.Hunter, D.B.Kireev,D.B.M.Miley,J.Norris-Drouin,W.M.Stewart,M.Lee,S.Sather, Y.Zhou,J.A.Dipaola,M.Machius,W.P.Janzen,H.S.Earp,D.K.Graham,S.Frye, X.Wang
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Key ref:
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W.Zhang
et al.
(2013).
Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis.
J Med Chem,
56,
9693-9700.
PubMed id:
DOI:
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Date:
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29-Aug-13
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Release date:
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21-May-14
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PROCHECK
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Headers
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References
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Q12866
(MERTK_HUMAN) -
Tyrosine-protein kinase Mer from Homo sapiens
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Seq:
Struc:
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999 a.a.
256 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.2.7.10.1
- receptor protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
56:9693-9700
(2013)
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PubMed id:
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Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis.
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W.Zhang,
A.L.McIver,
M.A.Stashko,
D.DeRyckere,
B.R.Branchford,
D.Hunter,
D.Kireev,
M.J.Miley,
J.Norris-Drouin,
W.M.Stewart,
M.Lee,
S.Sather,
Y.Zhou,
J.A.Di Paola,
M.Machius,
W.P.Janzen,
H.S.Earp,
D.K.Graham,
S.V.Frye,
X.Wang.
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ABSTRACT
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The role of Mer kinase in regulating the second phase of platelet activation
generates an opportunity to use Mer inhibitors for preventing thrombosis with
diminished likelihood for bleeding as compared to current therapies. Toward this
end, we have discovered a novel, Mer kinase specific substituted-pyrimidine
scaffold using a structure-based drug design and a pseudo ring replacement
strategy. The cocrystal structure of Mer with two compounds (7 and 22)
possessing distinct activity have been determined. Subsequent SAR studies
identified compound 23 (UNC2881) as a lead compound for in vivo evaluation. When
applied to live cells, 23 inhibits steady-state Mer kinase phosphorylation with
an IC50 value of 22 nM. Treatment with 23 is also sufficient to block
EGF-mediated stimulation of a chimeric receptor containing the intracellular
domain of Mer fused to the extracellular domain of EGFR. In addition, 23
potently inhibits collagen-induced platelet aggregation, suggesting that this
class of inhibitors may have utility for prevention and/or treatment of
pathologic thrombosis.
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