2FGI

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

2FGI の概要

• エントリーDOI: 10.2210/pdb2fgi/pdb
• 分子名称: 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)
• 機能のキーワード: protein kinase, tyrosine-protein kinase, atp-binding, phosphorylation, inhibitor, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P11362
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71664.57

構造登録者

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. (登録日: 1998-09-15, 公開日: 1999-09-13, 最終更新日: 2023-12-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.5 Å)