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PDBsum entry 5mjb
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PDB id:
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Transferase
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Title:
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Kinase domain of human ephb1, g703c mutant, covalently bound to a quinazoline-based inhibitor
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Structure:
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Ephrin type-b receptor 1. Chain: a, b. Synonym: elk,eph tyrosine kinase 2,eph-like kinase 6,hek6,neuronally- expressed eph-related tyrosine kinase,net,tyrosine-protein kinase receptor eph-2. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ephb1, elk, epht2, hek6, net. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: gold
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Resolution:
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2.23Å
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R-factor:
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0.199
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R-free:
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0.214
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Authors:
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A.Kung,M.Schimpl,Y.-C.Chen,R.C.Overman,C.Zhang
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Key ref:
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A.Kung
et al.
(2017).
A Chemical-Genetic Approach to Generate Selective Covalent Inhibitors of Protein Kinases.
ACS Chem Biol,
12,
1499-1503.
PubMed id:
DOI:
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Date:
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30-Nov-16
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Release date:
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17-May-17
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PROCHECK
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Headers
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References
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P54762
(EPHB1_HUMAN) -
Ephrin type-B receptor 1 from Homo sapiens
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Seq:
Struc:
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984 a.a.
278 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 3 residue positions (black
crosses)
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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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ACS Chem Biol
12:1499-1503
(2017)
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PubMed id:
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A Chemical-Genetic Approach to Generate Selective Covalent Inhibitors of Protein Kinases.
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A.Kung,
M.Schimpl,
A.Ekanayake,
Y.C.Chen,
R.Overman,
C.Zhang.
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ABSTRACT
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Although a previously developed bump-hole approach has proven powerful in
generating specific inhibitors for mapping functions of protein kinases, its
application is limited by the intolerance of the large-to-small mutation by
certain kinases and the inability to control two kinases separately in the same
cells. Herein, we describe the development of an alternative chemical-genetic
approach to overcome these limitations. Our approach features the use of an
engineered cysteine residue at a particular position as a reactive feature to
sensitize a kinase of interest to selective covalent blockade by electrophilic
inhibitors and is thus termed the Ele-Cys approach. We successfully applied the
Ele-Cys approach to identify selective covalent inhibitors of a receptor
tyrosine kinase EphB1 and solved cocrystal structures to determine the mode of
covalent binding. Importantly, the Ele-Cys and bump-hole approaches afforded
orthogonal inhibition of two distinct kinases in the cell, opening the door to
their combined use in the study of multikinase signaling pathways.
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