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PDBsum entry 5l6p
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PDB id:
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Transferase
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Title:
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Ephb3 kinase domain covalently bound to an irreversible inhibitor (compound 6)
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Structure:
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Ephrin type-b receptor 3. Chain: a. Synonym: eph-like tyrosine kinase 2,eph-like kinase 2,embryonic kinase 2,hek2,tyrosine-protein kinase tyro6. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ephb3, etk2, hek2, tyro6. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.26Å
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R-factor:
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0.206
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R-free:
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0.232
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Authors:
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M.Schimpl,R.Overman,A.Kung,Y.-C.Chen,F.Ni,J.Zhu,M.Turner,H.Molina, C.Zhang
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Key ref:
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A.Kung
et al.
(2016).
Development of Specific, Irreversible Inhibitors for a Receptor Tyrosine Kinase EphB3.
J Am Chem Soc,
138,
10554-10560.
PubMed id:
DOI:
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Date:
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30-May-16
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Release date:
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10-Aug-16
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PROCHECK
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Headers
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References
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P54753
(EPHB3_HUMAN) -
Ephrin type-B receptor 3 from Homo sapiens
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Seq:
Struc:
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998 a.a.
274 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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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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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 Am Chem Soc
138:10554-10560
(2016)
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PubMed id:
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Development of Specific, Irreversible Inhibitors for a Receptor Tyrosine Kinase EphB3.
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A.Kung,
Y.C.Chen,
M.Schimpl,
F.Ni,
J.Zhu,
M.Turner,
H.Molina,
R.Overman,
C.Zhang.
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ABSTRACT
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Erythropoietin-producing human hepatocellular carcinoma (Eph) receptor tyrosine
kinases (RTKs) regulate a variety of dynamic cellular events, including cell
protrusion, migration, proliferation, and cell-fate determination.
Small-molecule inhibitors of Eph kinases are valuable tools for dissecting the
physiological and pathological roles of Eph. However, there is a lack of
small-molecule inhibitors that are selective for individual Eph isoforms due to
the high homology within the family. Herein, we report the development of the
first potent and specific inhibitors of a single Eph isoform, EphB3. Through
structural bioinformatic analysis, we identified a cysteine in the hinge region
of the EphB3 kinase domain, a feature that is not shared with any other human
kinases. We synthesized and characterized a series of electrophilic quinazolines
to target this unique, reactive feature in EphB3. Some of the electrophilic
quinazolines selectively and potently inhibited EphB3 both in vitro and in
cells. Cocrystal structures of EphB3 in complex with two quinazolines confirmed
the covalent linkage between the protein and the inhibitors. A
"clickable" version of an optimized inhibitor was created and employed
to verify specific target engagement in the whole proteome and to probe the
extent and kinetics of target engagement of existing EphB3 inhibitors.
Furthermore, we demonstrate that the autophosphorylation of EphB3 within the
juxtamembrane region occurs in trans using a specific inhibitor. These
exquisitely specific inhibitors will facilitate the dissection of EphB3's role
in various biological processes and disease contribution.
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Links
