1TN8: Protein Farnesyltransferase Complexed With A H-Ras Peptide Substrate And A Fpp Analog At 2.25a Resolution

Post-translational modifications are essential for the proper function of many proteins in the cell. The attachment of an isoprenoid lipid (a process termed prenylation) by protein farnesyltransferase (FTase) or geranylgeranyltransferase type I (GGTase-I) is essential for the function of many signal transduction proteins involved in growth, differentiation, and oncogenesis. FTase and GGTase-I (also called the CaaX prenyltransferases) recognize protein substrates with a C-terminal tetrapeptide recognition motif called the Ca1a2X box. These enzymes possess distinct but overlapping protein substrate specificity that is determined primarily by the sequence identity of the Ca1a2X motif. To determine how the identity of the Ca1a2X motif residues and sequence upstream of this motif affect substrate binding, we have solved crystal structures of FTase and GGTase-I complexed with a total of eight cognate and cross-reactive substrate peptides, including those derived from the C termini of the oncoproteins K-Ras4B, H-Ras and TC21. These structures suggest that all peptide substrates adopt a common binding mode in the FTase and GGTase-I active site. Unexpectedly, while the X residue of the Ca1a2X motif binds in the same location for all GGTase-I substrates, the X residue of FTase substrates can bind in one of two different sites. Together, these structures outline a series of rules that govern substrate peptide selectivity; these rules were utilized to classify known protein substrates of CaaX prenyltransferases and to generate a list of hypothetical substrates within the human genome.
PDB ID: 1TN8Download
MMDB ID: 29947
PDB Deposition Date: 2004/6/11
Updated in MMDB: 2004/12
Experimental Method:
x-ray diffraction
Resolution: 2.25  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 1TN8: trimeric; determined by author and by software (PISA)
Molecular Components in 1TN8
Label Count Molecule
Proteins (3 molecules)
Protein Farnesyltransferasegeranylgeranyltransferase Type I Alpha Subunit(Gene symbol: Fnta)
Molecule annotation
Protein Farnesyltransferase Beta Subunit(Gene symbol: Fntb)
Molecule annotation
Peptide Derived From the C-terminus of H-ras
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB