4F65

Crystal structure of Human Fibroblast Growth Factor Receptor 1 Kinase domain in complex with compound 8

Summary for 4F65

• Entry DOI: 10.2210/pdb4f65/pdb
• Related: 4F63 4F64
• Descriptor: Fibroblast growth factor receptor 1, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: kinase, atp binding, phosphorylation, trans-membrane, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type I membrane protein: P11362
• Total number of polymer chains: 2
• Total formula weight: 72184.26

Authors

Norman, R.A.,Breed, J.,Ogg, D. (deposition date: 2012-05-14, release date: 2012-06-06, Last modification date: 2024-02-28)

Primary citation

Norman, R.A.,Schott, A.K.,Andrews, D.M.,Breed, J.,Foote, K.M.,Garner, A.P.,Ogg, D.,Orme, J.P.,Pink, J.H.,Roberts, K.,Rudge, D.A.,Thomas, A.P.,Leach, A.G.
Protein-Ligand Crystal Structures Can Guide the Design of Selective Inhibitors of the FGFR Tyrosine Kinase.
J.Med.Chem., 55:5003-5012, 2012

PubMed Abstract: The design of compounds that selectively inhibit a single kinase is a significant challenge, particularly for compounds that bind to the ATP site. We describe here how protein-ligand crystal structure information was able both to rationalize observed selectivity and to guide the design of more selective compounds. Inhibition data from enzyme and cellular screens and the crystal structures of a range of ligands tested during the process of identifying selective inhibitors of FGFR provide a step-by-step illustration of the process. Steric effects were exploited by increasing the size of ligands in specific regions in such a way as to be tolerated in the primary target and not in other related kinases. Kinases are an excellent target class to exploit such approaches because of the conserved fold and small side chain mobility of the active form.

PubMed: 22612866
DOI: 10.1021/jm3004043

Experimental method

X-RAY DIFFRACTION (2.26 Å)