2FGI

CRYSTAL STRUCTURE OF THE TYROSINE KINASE DOMAIN OF FGF RECEPTOR 1 IN COMPLEX WITH INHIBITOR PD173074

Summary for 2FGI

• Entry DOI: 10.2210/pdb2fgi/pdb
• Descriptor: PROTEIN (FIBROBLAST GROWTH FACTOR (FGF) RECEPTOR 1), 1-TERT-BUTYL-3-[6-(3,5-DIMETHOXY-PHENYL)-2-(4-DIETHYLAMINO-BUTYLAMINO)-PYRIDO[2,3-D]PYRIMIDIN-7-YL]-UREA (3 entities in total)
• Functional Keywords: protein kinase, tyrosine-protein kinase, atp-binding, phosphorylation, inhibitor, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P11362
• Total number of polymer chains: 2
• Total formula weight: 71664.57

Authors

Mohammadi, M.,Froum, S.,Hamby, J.M.,Schroeder, M.,Panek, R.L.,Lu, G.H.,Eliseenkova, A.V.,Green, D.,Schlessinger, J.,Hubbard, S.R. (deposition date: 1998-09-15, release date: 1999-09-13, Last modification date: 2023-12-27)

Primary citation

Mohammadi, M.,Froum, S.,Hamby, J.M.,Schroeder, M.C.,Panek, R.L.,Lu, G.H.,Eliseenkova, A.V.,Green, D.,Schlessinger, J.,Hubbard, S.R.
Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain.
EMBO J., 17:5896-5904, 1998

PubMed Abstract: Angiogenesis, the sprouting of new blood vessels from pre-existing ones, is an essential physiological process in development, yet also plays a major role in the progression of human diseases such as diabetic retinopathy, atherosclerosis and cancer. The effects of the most potent angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin and fibroblast growth factor (FGF) are mediated through cell surface receptors that possess intrinsic protein tyrosine kinase activity. In this report, we describe a synthetic compound of the pyrido[2,3-d]pyrimidine class, designated PD 173074, that selectively inhibits the tyrosine kinase activities of the FGF and VEGF receptors. We show that systemic administration of PD 173074 in mice can effectively block angiogenesis induced by either FGF or VEGF with no apparent toxicity. To elucidate the determinants of selectivity, we have determined the crystal structure of PD 173074 in complex with the tyrosine kinase domain of FGF receptor 1 at 2.5 A resolution. A high degree of surface complementarity between PD 173074 and the hydrophobic, ATP-binding pocket of FGF receptor 1 underlies the potency and selectivity of this inhibitor. PD 173074 is thus a promising candidate for a therapeutic angiogenesis inhibitor to be used in the treatment of cancer and other diseases whose progression is dependent upon new blood vessel formation.

PubMed: 9774334
DOI: 10.1093/emboj/17.20.5896

Experimental method

X-RAY DIFFRACTION (2.5 Å)