Abstract: Protein geranylgeranyl transferase type I (GGTase-I), a Ca1a2X prenyltransferase, is an essential enzyme in eukaryotes. GGTase-I catalyzes the carboxyl-terminal lipidation of over one hundred proteins, including many GTP-binding regulatory proteins (G proteins). The presently disclosed subject matter comprises a plurality of crystal structures of mammalian GGTase-I in complex with substrates and products that provide the first structural information for this enzyme, facilitating the elucidation of a generalized method of action for all protein prenyltransferases; the method includes a role in product transport. The structures reveal specificity determinants that allow classification of putative protein prenyltransferase sequences and can facilitate optimization of GGTase-I and FTase modulators.