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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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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 human fibroblast growth factor receptor 1 kinase domain in complex with pyrazolaminopyrimidine 1
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Structure:
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Fibroblast growth factor receptor 1. Chain: a, b. Fragment: kinase domain (unp residues 458-765). Synonym: fgfr-1, basic fibroblast growth factor receptor 1, b bfgf-r- 1, fms-like tyrosine kinase 2, flt-2, n-sam, proto-onc fgr. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: fgfr1, bfgfr, cek, fgfbr, flg, flt2, hbgfr. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.57Å
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R-factor:
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0.209
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R-free:
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0.262
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Authors:
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R.A.Norman,T.Klein
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Key ref:
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T.Klein
et al.
(2014).
FGFR1 Kinase Inhibitors: Close Regioisomers Adopt Divergent Binding Modes and Display Distinct Biophysical Signatures.
Acs Med Chem Lett,
5,
166-171.
PubMed id:
DOI:
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Date:
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12-Nov-13
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Release date:
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18-Dec-13
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PROCHECK
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Headers
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References
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P11362
(FGFR1_HUMAN) -
Fibroblast growth factor receptor 1 from Homo sapiens
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Seq:
Struc:
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822 a.a.
281 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 1 residue position (black
cross)
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Enzyme class:
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E.C.2.7.10.1
- receptor 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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Acs Med Chem Lett
5:166-171
(2014)
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PubMed id:
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FGFR1 Kinase Inhibitors: Close Regioisomers Adopt Divergent Binding Modes and Display Distinct Biophysical Signatures.
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T.Klein,
J.Tucker,
G.A.Holdgate,
R.A.Norman,
A.L.Breeze.
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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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