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PDBsum entry 7ajs
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PDB id:
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Transferase
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Title:
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Structure of dyrk1a in complex with compound 33
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Structure:
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Dual specificity tyrosine-phosphorylation-regulated kinase 1a. Chain: a, b. Synonym: dual specificity yak1-related kinase,hp86,protein kinase minibrain homolog,hmnb. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: dyrk1a, dyrk, mnb, mnbh. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_cell_line: plyss
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Resolution:
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2.15Å
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R-factor:
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0.163
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R-free:
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0.200
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Authors:
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P.Dokurno,A.E.Surgenor,A.Kotschy
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Key ref:
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C.Weber
et al.
(2021).
Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors.
J Med Chem,
64,
6745-6764.
PubMed id:
DOI:
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Date:
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29-Sep-20
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Release date:
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26-May-21
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PROCHECK
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Headers
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References
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Q13627
(DYR1A_HUMAN) -
Dual specificity tyrosine-phosphorylation-regulated kinase 1A from Homo sapiens
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Seq:
Struc:
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763 a.a.
337 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 2:
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E.C.2.7.11.23
- [RNA-polymerase]-subunit kinase.
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Reaction:
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[DNA-directed RNA polymerase] + ATP = phospho-[DNA-directed RNA polymerase] + ADP + H+
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[DNA-directed RNA polymerase]
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+
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ATP
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=
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phospho-[DNA-directed RNA polymerase]
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+
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ADP
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+
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H(+)
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Enzyme class 3:
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E.C.2.7.12.1
- dual-specificity kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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3.
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
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+
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ADP
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+
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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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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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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
64:6745-6764
(2021)
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PubMed id:
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Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors.
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C.Weber,
M.Sipos,
A.Paczal,
B.Balint,
V.Kun,
N.Foloppe,
P.Dokurno,
A.J.Massey,
D.L.Walmsley,
R.E.Hubbard,
J.Murray,
K.Benwell,
T.Edmonds,
D.Demarles,
A.Bruno,
M.Burbridge,
F.Cruzalegui,
A.Kotschy.
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ABSTRACT
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The kinase DYRK1A is an attractive target for drug discovery programs due to its
implication in multiple diseases. Through a fragment screen, we identified a
simple biaryl compound that is bound to the DYRK1A ATP site with very high
efficiency, although with limited selectivity. Structure-guided optimization
cycles enabled us to convert this fragment hit into potent and selective DYRK1A
inhibitors. Exploiting the structural differences in DYRK1A and its close
homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors.
Our best compounds potently inhibited DYRK1A in the cell culture and in
vivo and demonstrated drug-like properties. The inhibition of DYRK1A in
vivo translated into dose-dependent tumor growth inhibition in a model of
ovarian carcinoma.
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