1SA5

Rat protein farnesyltransferase complexed with FPP and BMS-214662

1SA5 の概要

• エントリーDOI: 10.2210/pdb1sa5/pdb
• 関連するPDBエントリー: 1D8D 1FT1 1JCQ 1JCR 1LD8 1O5M 1SA4
• 分子名称: Protein farnesyltransferase/geranylgeranyltransferase type I alpha subunit, Protein farnesyltransferase beta subunit, ZINC ION, ... (7 entities in total)
• 機能のキーワード: ftase, farnesyltransferase, farnesyl transferase, caax, ras, cancer, tumor regression, bms-214662, fti, clinical candidate, inhibitor, protein prenylation, lipid modification, transferase
• 由来する生物種: Rattus norvegicus (Norway rat); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 93817.82

構造登録者

Reid, T.S.,Beese, L.S. (登録日: 2004-02-06, 公開日: 2004-06-08, 最終更新日: 2023-08-23)

主引用文献

Reid, T.S.,Beese, L.S.
Crystal Structures of the Anticancer Clinical Candidates R115777 (Tipifarnib) and BMS-214662 Complexed with Protein Farnesyltransferase Suggest a Mechanism of FTI Selectivity.
Biochemistry, 43:6877-6884, 2004

PubMed Abstract: The search for new cancer therapeutics has identified protein farnesyltransferase (FTase) as a promising drug target. This enzyme attaches isoprenoid lipids to signal transduction proteins involved in growth and differentiation. The two FTase inhibitors (FTIs), R115777 (tipifarnib/Zarnestra) and BMS-214662, have undergone evaluation as cancer therapeutics in phase I and II clinical trials. R115777 has been evaluated in phase III clinical trials and shows indications for the treatment of blood and breast malignancies. Here we present crystal structures of R115777 and BMS-214662 complexed with mammalian FTase. These structures illustrate the molecular mechanism of inhibition and selectivity toward FTase over the related enzyme, protein geranylgeranyltransferase type I (GGTase-I). These results, combined with previous biochemical and structural analyses, identify features of FTase that could be exploited to modulate inhibitor potency and specificity and should aid in the continued development of FTIs as therapeutics for the treatment of cancer and parasitic infections.

PubMed: 15170324
DOI: 10.1021/bi049723b

実験手法

X-RAY DIFFRACTION (2.6 Å)