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PDBsum entry 4rfz
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Transferase/transferase inhibitor
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PDB id
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4rfz
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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- (dimethylamino)-8-fluoro-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5- (morpholine-4-carbonyl)-2-pyridyl]amino]-6-oxo-3- pyridyl]phenyl]isoquinolin-1-one
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Structure:
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Tyrosine-protein kinase btk. Chain: a. Fragment: protein kinase domain (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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1.17Å
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R-factor:
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0.158
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R-free:
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0.184
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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).
Finding the perfect spot for fluorine: improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffold.
Bioorg Med Chem Lett,
25,
367-371.
PubMed id:
DOI:
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Date:
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29-Sep-14
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Release date:
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24-Dec-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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Bioorg Med Chem Lett
25:367-371
(2015)
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PubMed id:
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Finding the perfect spot for fluorine: improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffold.
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Y.Lou,
Z.K.Sweeney,
A.Kuglstatter,
D.Davis,
D.M.Goldstein,
X.Han,
J.Hong,
B.Kocer,
R.K.Kondru,
R.Litman,
J.McIntosh,
K.Sarma,
J.Suh,
J.Taygerly,
T.D.Owens.
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ABSTRACT
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A rational fluorine scan based on co-crystal structures was explored to increase
the potency of a series of selective BTK inhibitors. While fluorine substitution
on a saturated bicyclic ring system yields no apparent benefit, the same
operation on an unsaturated bicyclic ring can increase HWB activity by up to
40-fold. Comparison of co-crystal structures of parent molecules and fluorinated
counterparts revealed the importance of placing fluorine at the optimal position
to achieve favorable interactions with protein side chains.
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Links
