Zinc-containing enzymes crystallography

The structure and mechanism of catalysis of FTase were well defined in the late 1990s from several X-ray crystallography and elegant biochemical studies [24,26-30]. The enzyme is a heterodimer of a and P subunits [31,32]. The P subunit contains binding sites for both the farnesyl pyrophosphate and the CAAX protein substrates. A catalytic zinc (Zn " ) identified in the active site of the P subunit participates in the binding and activation of the CAAX protein substrates [28]. The Zn " is coordinated to the enzyme in a distorted tetrahedral geometry and surrounded by hydrophobic pockets [24,27]. Upon binding of the CAAX peptide, the thiol of the cysteine displaces water and is activated for a nucleophilic attack via thiolate on the C-1 carbon atom of farnesyl pyrophosphate [30]. 

In the last couple of years, several advances in our understanding on a molecular level of how lead inhibits this important enzyme have been made. The structure of the zinc- and lead-bound forms of yeast ALAD have been determined by X-ray crystallography. These structures reveal that lead substitutes for zinc in the catalytic site of the enzyme (Fig. 17) (245). The crystal structure also resolved an on-going debate about the nature of the metal-binding residues in the catalytic site in ALAD The active site contains three cysteine... 

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