PDBsum entry 1ft1

Transferase

PDB id

1ft1

Contents

			Protein chains

					315 a.a. *


					416 a.a. *

			Metals

					_ZN

			Waters ×402

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Crystal structure of protein farnesyltransferase at 2.25 angstrom resolution.

Authors

H.W.Park, S.R.Boduluri, J.F.Moomaw, P.J.Casey, L.S.Beese.

Ref.

Science, 1997, 275, 1800-1804. [DOI no: 10.1126/science.275.5307.1800]

PubMed id

9065406

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.



	Figure 2. Fig. 2. The subunit. (A) Aromatic pocket in the center of the - barrel of the subunit. This view is a 90° clockwise^ rotation relative to Fig. 1A. Only helices 2 to 13 are shown. Yellow, the nine aromatic residues that line the pocket; magenta, the zinc ion [MOLSCRIPT (40) and RASTER3D (41)]. (B) A portion of the solvent-accessible surface showing some of the^ aromatic residues that line the putative FPP binding pocket. FPP is modeled with the isoprenoid in the hydrophobic cleft and the^ diphosphate moiety positioned near the zinc. The carbon atoms of FPP are yellow, oxygens are red, and phosphates are green. The program INSIGHT II (43) was used to construct an energy-minimized^ model of FPP and GRASP (44) was used to calculate the accessible^ surface.		Figure 3. Fig. 3. (A) Solvent-accessible surface and electrostatic surface potential. The dashed box highlights the cleft where the^ nonapeptide binds. The most negative electrostatic surface potential (-10 kT) is colored red. The most positive electrostatic surface^ potential (10 kT) is blue. The orientation is similar to that of Fig. 1. The arrow indicates the putative FPP binding site [GRASP (44)]. (B) Close-up view of the nonapeptide binding cleft bounded by the dashed lines in (A). The COOH-terminus and six residues of the nonapeptide (Ala^9-Val8-Thr7-Ser6-Asp5-Pro4) are visible. Atom colors for the nonapeptide are coral, carbons; red, oxygen; light blue, nitrogen; and zinc, magenta. (C) Stereo view of the nonapeptide (COOH-terminus of a symmetry-related^ subunit). The nonapeptide is numbered from the COOH-terminus. Atom colors in the nonapeptide are coral, carbons; orange, oxygen; and light blue, nitrogen. Atom colors of residues forming the^ binding pocket are khaki, carbons; red, oxygen; and blue, nitrogen. Zinc is a magenta sphere. Water molecules are red spheres. Dotted^ lines represent potential hydrogen bonds.