Long Stephen B, Casey Patrick J, Beese Lorena S
Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nature. 2002 Oct 10;419(6907):645-50. doi: 10.1038/nature00986.
Protein farnesyltransferase (FTase) catalyses the attachment of a farnesyl lipid group to numerous essential signal transduction proteins, including members of the Ras superfamily. The farnesylation of Ras oncoproteins, which are associated with 30% of human cancers, is essential for their transforming activity. FTase inhibitors are currently in clinical trials for the treatment of cancer. Here we present a complete series of structures representing the major steps along the reaction coordinate of this enzyme. From these observations can be deduced the determinants of substrate specificity and an unusual mechanism in which product release requires binding of substrate, analogous to classically processive enzymes. A structural model for the transition state consistent with previous mechanistic studies was also constructed. The processive nature of the reaction suggests the structural basis for the successive addition of two prenyl groups to Rab proteins by the homologous enzyme geranylgeranyltransferase type-II. Finally, known FTase inhibitors seem to differ in their mechanism of inhibiting the enzyme.
蛋白质法尼基转移酶（FTase）催化法尼基脂质基团连接到众多重要的信号转导蛋白上，包括Ras超家族的成员。Ras癌蛋白的法尼基化与30%的人类癌症相关，对其转化活性至关重要。FTase抑制剂目前正处于癌症治疗的临床试验阶段。在此，我们展示了一系列完整的结构，代表了该酶反应坐标上的主要步骤。从这些观察结果中可以推断出底物特异性的决定因素以及一种不同寻常的机制，即产物释放需要底物结合，这类似于经典的持续性酶。还构建了一个与先前机制研究一致的过渡态结构模型。该反应的持续性性质提示了同源酶II型香叶基香叶基转移酶将两个异戊二烯基连续添加到Rab蛋白上的结构基础。最后，已知的FTase抑制剂在抑制该酶的机制上似乎有所不同。
