Drug Discovery Today  Volume 20, Number 2  February 2015 REVIEWS Farnesyltransferase and geranylgeranyltransferase I: structures, mechanism, inhibitors and molecular modeling Mingyun Shen 1,2 , Peichen Pan 1,2 , Youyong Li 1 , Dan Li 2 , Huidong Yu 3 and Tingjun Hou 1,2 1 Institute of Functional Nano and Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China 2 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China 3 Crystal Pharmatech, 707 Alexander Road Building 2, Suite 208, Princeton, NJ 08540, USA Farnesyltransferase (FTase) and geranylgeranyltransferase type I (GGTase-I) have crucial roles in the post-translational modifications of Ras proteins and, therefore, they are promising therapeutic targets for the treatment of various Ras-induced cancers and several other kinds of diseases. In this review, we provide an overview of the structures and biological functions of FTase and GGTase-I. Then, we summarize the typical inhibitors of FTase and GGTase-I, and highlight the drug candidates in clinical trials. In addition, we survey some recent advances in computer-aided drug design (CADD) and molecular modeling studies of FTase and GGTase-I. Introduction Ras is an oncoprotein and plays an important part in cellular signaling pathways [1]. Once mutated, it can cause a series of biological and pathological reactions, which might result in nu- merous cancers [2,3]. Therefore, development of anticancer drugs targeting Ras signaling pathways is of great therapeutic impor- tance. Previous studies have revealed that the post-translational Ras oncoprotein is modified by a 15-carbon farnesyl group or a 20- carbon geranylgeranyl group, catalyzed by farnesyltransferase (FTase) or geranylgeranyltransferase type I (GGTase-I) [4,5]. FTase and GGTase-I are prenyltransferases that target the carboxyl-ter- minal cysteine residues of the proteins with the CAAX motif (C refers to cysteine, A refers to any aliphatic amino acid and X refers to any amino acid) [6]. Owing to the essential roles of FTase and GGTase-I in the post-translational modifications of Ras proteins, a number of prenyltransferase inhibitors have been discovered and developed for the treatment of cancers [7,8], progeria [9], malaria [10], Trypanosoma cruzi [11], toxoplasmosis [12] and leishmaniasis [13]. In this review, the structures, biological functions and typical inhibitors of FTase and GGTase-I are summarized. In addition, recent advances in computer-aided drug design (CADD) and mo- lecular modeling studies of FTase and GGTase-I are discussed. FTase and GGTase-I: structures and biological and enzymatic activities Structures of FTase and GGTase-I FTase and GGTase-I are heterodimers, formed by an a subunit and a b subunit (Fig. 1a) [14], which are primarily composed of a helices that are arranged into different shapes. The a subunit is a crescent-shaped super helix, whereas the b subunit is an a–a barrel [15]. The 48 kDa a subunits of FTase and GGTase-I are almost identical [16], but the b subunits of FTase and GGTase-I are different [17]. The sequence identity of the b subunits of FTase and GGTase-I is 30%, but the homology between the central regions of FTase and GGTase-I is relatively higher. The b subunits of FTase and GGTase-I consist of 14 and 13 a helices, respectively, with 12 a helices folded into an a–a barrel. This arrangement forms a funnel-shaped cavity in the center of the barrel, where the active sites of FTase and GGTase-I are located. This cavity is hydrophobic and contains a number of conserved aromatic resi- dues. The N-terminal domain is disordered and proline-rich, and has no direct influence on the catalytic activity. Binding sites of FTase and GGTase-I As prenyltransferases, FTase and GGTase-I can transfer isoprenoids to intracellular proteins that contain CAAX motifs. Thus, FTase and GGTase-I have two substrates: one is an isoprenoid substrate and the other is a protein substrate [18]. A zinc ion, which binds to Reviews  POST SCREEN Corresponding authors: Yu, H. (huidongyu@yahoo.com), Hou, T. (tingjunhou@zju.edu.cn, tingjunhou@hotmail.com) 1359-6446/06/$ - see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2014.10.002 www.drugdiscoverytoday.com 267