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Crystal structure of protein farnesyltransferase at 2.25 angstrom resolution
H W Park1, S R Boduluri, J F Moomaw
1Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
Abstract:
Protein farnesyltransferase (FTase) catalyzes the carboxyl-terminal lipidation of Ras and several other cellular signal transduction proteins. The essential nature of this modification for proper function of these proteins has led to the emergence of FTase as a target for the development of new anticancer therapy. Inhibition of this enzyme suppresses the transformed phenotype in cultured cells and causes tumor regression in animal models. The crystal structure of heterodimeric mammalian FTase was determined at 2.25 angstrom resolution. The structure shows a combination of two unusual domains: a crescent-shaped seven-helical hairpin domain and an alpha-alpha barrel domain. The active site is formed by two clefts that intersect at a bound zinc ion. One cleft contains a nine-residue peptide that may mimic the binding of the Ras substrate; the other cleft is lined with highly conserved aromatic residues appropriate for binding the farnesyl isoprenoid with required specificity.
Insights
Protein farnesyltransferase (FTase) is a key enzyme in cell signaling and a target for cancer therapy. Its crystal structure reveals an active site with two clefts, offering insights for developing novel anticancer drugs.
Area of Science:
- Biochemistry
- Structural Biology
- Oncology
Background:
- Protein farnesyltransferase (FTase) catalyzes essential protein lipidation for cellular signal transduction.
- FTase is a validated target for anticancer drug development due to its role in cancer cell transformation.
Purpose of the Study:
- To determine the crystal structure of heterodimeric mammalian FTase.
- To elucidate the structural basis for FTase substrate binding and inhibition.
Main Methods:
- X-ray crystallography was used to determine the three-dimensional structure of mammalian FTase.
- High-resolution (2.25 angstrom) structural analysis was performed.
Main Results:
- The crystal structure revealed a unique combination of a crescent-shaped seven-helical hairpin domain and an alpha-alpha barrel domain.
- The active site features two intersecting clefts around a zinc ion, with one cleft potentially binding the Ras substrate and the other the farnesyl group.
Conclusions:
- The determined FTase structure provides a detailed molecular understanding of its active site.
- This structural information is crucial for the rational design of specific FTase inhibitors for cancer therapy.