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PDBsum entry 4nk9
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Transferase/transferase inhibitor
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PDB id
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4nk9
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References listed in PDB file
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Key reference
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Title
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Fgfr1 kinase inhibitors: close regioisomers adopt divergent binding modes and display distinct biophysical signatures.
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Authors
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T.Klein,
J.Tucker,
G.A.Holdgate,
R.A.Norman,
A.L.Breeze.
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Ref.
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Acs Med Chem Lett, 2014,
5,
166-171.
[DOI no: ]
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PubMed id
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Abstract
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The binding of a ligand to its target protein is often accompanied by
conformational changes of both the protein and the ligand. This is of particular
interest, since structural rearrangements of the macromolecular target and the
ligand influence the free energy change upon complex formation. In this study,
we use X-ray crystallography, isothermal titration calorimetry, and
surface-plasmon resonance biosensor analysis to investigate the binding of
pyrazolylaminopyrimidine inhibitors to FGFR1 tyrosine kinase, an important
anticancer target. Our results highlight that structurally close analogs of this
inhibitor series interact with FGFR1 with different binding modes, which are a
consequence of conformational changes in both the protein and the ligand as well
as the bound water network. Together with the collected kinetic and
thermodynamic data, we use the protein-ligand crystal structure information to
rationalize the observed inhibitory potencies on a molecular level.
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