Structure of mammalian protein geranylgeranyltransferase type-I

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Abstract
Protein geranylgeranyltransferase type‐I (GGTase‐I), one of two CaaX prenyltransferases, is an essential enzyme in eukaryotes. GGTase‐I catalyzes C‐terminal lipidation of >100 proteins, including many GTP‐ binding regulatory proteins. We present the first structural information for mammalian GGTase‐I, including a series of substrate and product complexes that delineate the path of the chemical reaction. These structures reveal that all protein prenyltransferases share a common reaction mechanism and identify specific residues that play a dominant role in determining prenyl group specificity. This hypothesis was confirmed by converting farnesyltransferase (15‐C prenyl substrate) into GGTase‐I (20‐C prenyl substrate) with a single point mutation. GGTase‐I discriminates against farnesyl diphosphate (FPP) at the product turnover step through the inability of a 15‐C FPP to displace the 20‐C prenyl‐peptide product. Understanding these key features of specificity is expected to contribute to optimization of anti‐cancer and anti‐parasite drugs.