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PDBsum entry 4otr
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Transferase/transferase inhibitor
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PDB id
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4otr
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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 btk kinase domain complexed with 6-cyclopropyl-2- [3-[5-[[5-(4-ethylpiperazin-1-yl)-2-pyridyl]amino]-1-methyl-6-oxo-3- pyridyl]-2-(hydroxymethyl)phenyl]-8-fluoro-isoquinolin-1-one
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Structure:
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Tyrosine-protein kinase btk. Chain: a. Fragment: unp residues 378-659. Synonym: agammaglobulinemia tyrosine kinase, atk, b-cell progenitor kinase, bpk, bruton tyrosine kinase. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: btk, agmx1, atk, bpk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
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Resolution:
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1.95Å
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R-factor:
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0.183
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R-free:
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0.229
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Authors:
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A.Kuglstatter,A.Wong
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Key ref:
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Y.Lou
et al.
(2015).
Structure-based drug design of RN486, a potent and selective Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritis.
J Med Chem,
58,
512-516.
PubMed id:
DOI:
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Date:
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14-Feb-14
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Release date:
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14-May-14
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PROCHECK
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Headers
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References
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Q06187
(BTK_HUMAN) -
Tyrosine-protein kinase BTK from Homo sapiens
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Seq:
Struc:
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659 a.a.
263 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 4 residue positions (black
crosses)
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Enzyme class:
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E.C.2.7.10.2
- non-specific 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
58:512-516
(2015)
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PubMed id:
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Structure-based drug design of RN486, a potent and selective Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritis.
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Y.Lou,
X.Han,
A.Kuglstatter,
R.K.Kondru,
Z.K.Sweeney,
M.Soth,
J.McIntosh,
R.Litman,
J.Suh,
B.Kocer,
D.Davis,
J.Park,
S.Frauchiger,
N.Dewdney,
H.Zecic,
J.P.Taygerly,
K.Sarma,
J.Hong,
R.J.Hill,
T.Gabriel,
D.M.Goldstein,
T.D.Owens.
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ABSTRACT
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Structure-based drug design was used to guide the optimization of a series of
selective BTK inhibitors as potential treatments for Rheumatoid arthritis.
Highlights include the introduction of a benzyl alcohol group and a fluorine
substitution, each of which resulted in over 10-fold increase in activity.
Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J.
Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced
preclinical characterization based on its favorable properties.
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