Park H W, Boduluri S R, Moomaw J F, Casey P J, Beese L S
Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
Science. 1997 Mar 21;275(5307):1800-4. doi: 10.1126/science.275.5307.1800.
Protein farnesyltransferase (FTase) catalyzes the carboxyl-terminal lipidation of Ras and several other cellular signal transduction proteins. The essential nature of this modification for proper function of these proteins has led to the emergence of FTase as a target for the development of new anticancer therapy. Inhibition of this enzyme suppresses the transformed phenotype in cultured cells and causes tumor regression in animal models. The crystal structure of heterodimeric mammalian FTase was determined at 2.25 angstrom resolution. The structure shows a combination of two unusual domains: a crescent-shaped seven-helical hairpin domain and an alpha-alpha barrel domain. The active site is formed by two clefts that intersect at a bound zinc ion. One cleft contains a nine-residue peptide that may mimic the binding of the Ras substrate; the other cleft is lined with highly conserved aromatic residues appropriate for binding the farnesyl isoprenoid with required specificity.
蛋白质法尼基转移酶（FTase）催化Ras及其他几种细胞信号转导蛋白的羧基末端脂化反应。这种修饰对于这些蛋白质正常功能的重要性，使得FTase成为新型抗癌疗法开发的靶点。抑制该酶可抑制培养细胞中的转化表型，并在动物模型中导致肿瘤消退。异源二聚体哺乳动物FTase的晶体结构在2.25埃分辨率下得以确定。该结构显示出两个不同寻常结构域的组合：一个新月形的七螺旋发夹结构域和一个α-α桶状结构域。活性位点由在结合的锌离子处相交的两个裂缝形成。一个裂缝包含一个九肽，可能模拟Ras底物的结合；另一个裂缝则排列着高度保守的芳香族残基，适合以所需的特异性结合法尼基类异戊二烯。
