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PDBsum entry 7ab0
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PDB id:
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Transferase
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Title:
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Apo crystal structure of the mertk kinase domain
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Structure:
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Tyrosine-protein kinase mer. Chain: a. Fragment: mertk kinase domain. Synonym: proto-oncogenE C-mer,receptor tyrosine kinase mertk. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: mertk, mer. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: star.
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Resolution:
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1.74Å
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R-factor:
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0.202
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R-free:
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0.247
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Authors:
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A.Pflug,M.Schimpl,W.Mccoull,J.W.M.Nissink,R.C.Overman,P.B.Rawlins, C.Truman,E.Underwood,J.Warwicker,J.Winter-Holt
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Key ref:
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A.Pflug
et al.
(2020).
A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding.
Biochem J,
477,
4443-4452.
PubMed id:
DOI:
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Date:
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05-Sep-20
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Release date:
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28-Oct-20
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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.
271 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 8 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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Biochem J
477:4443-4452
(2020)
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PubMed id:
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A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding.
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A.Pflug,
M.Schimpl,
J.W.M.Nissink,
R.C.Overman,
P.B.Rawlins,
C.Truman,
E.Underwood,
J.Warwicker,
J.Winter-Holt,
W.McCoull.
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ABSTRACT
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The activation loop (A-loop) plays a key role in regulating the catalytic
activity of protein kinases. Phosphorylation in this region enhances the
phosphoryl transfer rate of the kinase domain and increases its affinity for
ATP. Furthermore, the A-loop possesses autoinhibitory functions in some kinases,
where it collapses onto the protein surface and blocks substrate binding when
unphosphorylated. Due to its flexible nature, the A-loop is usually disordered
and untraceable in kinase domain crystal structures. The resulting lack of
structural information is regrettable as it impedes the design of drug A-loop
contacts, which have proven favourable in multiple cases. Here, we characterize
the binding with A-loop engagement between type 1.5 kinase inhibitor 'example
172' (EX172) and Mer tyrosine kinase (MerTK). With the help of crystal
structures and binding kinetics, we portray how the recruitment of the A-loop
elicits a two-step binding mechanism which results in a drug-target complex
characterized by high affinity and long residence time. In addition, the type
1.5 compound possesses excellent kinome selectivity and a remarkable preference
for the phosphorylated over the dephosphorylated form of MerTK. We discuss these
unique characteristics in the context of known type 1 and type 2 inhibitors and
highlight opportunities for future kinase inhibitor design.
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