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PDBsum entry 4ebw
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Transferase/transferase inhibitor
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PDB id
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4ebw
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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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Structure of focal adhesion kinase catalytic domain in complex with novel allosteric inhibitor
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Structure:
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Focal adhesion kinase 1. Chain: a. Fragment: unp residues 411-686. Synonym: fadk 1, focal adhesion kinase-related nonkinase, frnk, protein phosphatase 1 regulatory subunit 71, ppp1r71, protein- tyrosine kinase 2, p125fak, pp125fak. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ptk2, fak, fak1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
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Resolution:
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2.65Å
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R-factor:
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0.186
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R-free:
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0.273
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Authors:
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M.Iwatani,H.Iwata,A.Okabe,R.J.Skene,N.Tomita,Y.Hayashi,Y.Aramaki, D.J.Hosfield,A.Hori,A.Baba,H.Miki
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Key ref:
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M.Iwatani
et al.
(2013).
Discovery and characterization of novel allosteric FAK inhibitors.
Eur J Med Chem,
61,
49-60.
PubMed id:
DOI:
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Date:
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25-Mar-12
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Release date:
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25-Jul-12
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PROCHECK
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Headers
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References
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Q05397
(FAK1_HUMAN) -
Focal adhesion kinase 1 from Homo sapiens
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Seq:
Struc:
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1052 a.a.
259 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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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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Eur J Med Chem
61:49-60
(2013)
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PubMed id:
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Discovery and characterization of novel allosteric FAK inhibitors.
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M.Iwatani,
H.Iwata,
A.Okabe,
R.J.Skene,
N.Tomita,
Y.Hayashi,
Y.Aramaki,
D.J.Hosfield,
A.Hori,
A.Baba,
H.Miki.
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ABSTRACT
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Focal adhesion kinase (FAK) regulates cell survival and proliferation pathways.
Here we report the discovery of a highly selective series of
1,5-dihydropyrazolo[4,3-c][2,1]benzothiazines that demonstrate a novel mode of
allosteric inhibition of FAK. These compounds showed slow dissociation from
unphosphorylated FAK and were noncompetitive with ATP after long preincubation.
Co-crystal structural analysis revealed that the compounds target a novel
allosteric site within the C-lobe of the kinase domain, which induces disruption
of ATP pocket formation leading to the inhibition of kinase activity. The
potency of allosteric inhibition was reduced by phosphorylation of FAK. Coupled
SAR analysis revealed that N-substitution of the fused pyrazole is critical to
achieve allosteric binding and high selectivity among kinases.
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Links
