3JS2

Crystal structure of minimal kinase domain of fibroblast growth factor receptor 1 in complex with 5-(2-thienyl)nicotinic acid

Summary for 3JS2

• Entry DOI: 10.2210/pdb3js2/pdb
• Descriptor: Basic fibroblast growth factor receptor 1, 5-(2-thienyl)nicotinic acid, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: fibroblast growth factor, receptor tyrosine kinase, inhibitor, thienyl nicotinic acid, alternative splicing, atp-binding, chromosomal rearrangement, craniosynostosis, disease mutation, disulfide bond, dwarfism, glycoprotein, heparin-binding, hypogonadotropic hypogonadism, immunoglobulin domain, kallmann syndrome, kinase, membrane, nucleotide-binding, phosphoprotein, polymorphism, receptor, transferase, transmembrane, tyrosine-protein kinase
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P11362
• Total number of polymer chains: 2
• Total formula weight: 73053.61

Authors

Bae, J.H.,Ravindranathan, K.P.,Mandiyan, V.,Ekkati, A.R.,Schlessinger, J.,Jorgensen, W.L. (deposition date: 2009-09-09, release date: 2010-02-23, Last modification date: 2023-09-20)

Primary citation

Ravindranathan, K.P.,Mandiyan, V.,Ekkati, A.R.,Bae, J.H.,Schlessinger, J.,Jorgensen, W.L.
Discovery of novel fibroblast growth factor receptor 1 kinase inhibitors by structure-based virtual screening
J.Med.Chem., 53:1662-1672, 2010

PubMed Abstract: Fibroblast growth factors (FGFs) play important roles in embryonic development, angiogenesis, wound healing, and cell proliferation and differentiation. In search of inhibitors of FGFR1 kinase, 2.2 million compounds were docked into the ATP binding site of the protein. A co-crystal structure, which shows two alternative conformations for the nucleotide binding loop, is reported. Docking was performed on both conformations and, ultimately, 23 diverse compounds were purchased and assayed. Following hit validation, two compounds 10 and 16, a benzylidene derivative of pseudothiohydantoin and a thienopyrimidinone derivative, respectively, were discovered that inhibit FGFR1 kinase with IC(50) values of 23 and 50 microM. Initial optimization of 16 led to the more unsaturated 40, which has significantly enhanced potency, 1.9 microM. The core structures represent new structural motifs for FGFR1 kinase inhibitors. The study also illustrates complexities associated with the choice of protein structures for docking, possible use of multiple kinase structures to seek selectivity, and hit identification.

PubMed: 20121196
DOI: 10.1021/jm901386e

Experimental method

X-RAY DIFFRACTION (2.2 Å)