2fgi
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CRYSTAL STRUCTURE OF THE TYROSINE KINASE DOMAIN OF FGF RECEPTOR 1 IN COMPLEX WITH INHIBITOR PD173074
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Atopic dermatitis, susceptibility to OMIM:[135940], Ichthyosis vulgaris OMIM:[135940], Jackson-Weiss syndrome OMIM:[136350], Kallmann syndrome 2 OMIM:[136350], Pfeiffer syndrome OMIM:[136350]
About this StructureAbout this Structure
2FGI is a Single protein structure of sequence from Homo sapiens with PD1 as ligand. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain., Mohammadi M, Froum S, Hamby JM, Schroeder MC, Panek RL, Lu GH, Eliseenkova AV, Green D, Schlessinger J, Hubbard SR, EMBO J. 1998 Oct 15;17(20):5896-904. PMID:9774334
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