1SA5

Rat protein farnesyltransferase complexed with FPP and BMS-214662

Summary for 1SA5

• Entry DOI: 10.2210/pdb1sa5/pdb
• Related: 1D8D 1FT1 1JCQ 1JCR 1LD8 1O5M 1SA4
• Descriptor: Protein farnesyltransferase/geranylgeranyltransferase type I alpha subunit, Protein farnesyltransferase beta subunit, ZINC ION, ... (7 entities in total)
• Functional Keywords: ftase, farnesyltransferase, farnesyl transferase, caax, ras, cancer, tumor regression, bms-214662, fti, clinical candidate, inhibitor, protein prenylation, lipid modification, transferase
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 2
• Total formula weight: 93817.82

Authors

Reid, T.S.,Beese, L.S. (deposition date: 2004-02-06, release date: 2004-06-08, Last modification date: 2023-08-23)

Primary citation

Reid, T.S.,Beese, L.S.
Crystal Structures of the Anticancer Clinical Candidates R115777 (Tipifarnib) and BMS-214662 Complexed with Protein Farnesyltransferase Suggest a Mechanism of FTI Selectivity.
Biochemistry, 43:6877-6884, 2004

PubMed Abstract: The search for new cancer therapeutics has identified protein farnesyltransferase (FTase) as a promising drug target. This enzyme attaches isoprenoid lipids to signal transduction proteins involved in growth and differentiation. The two FTase inhibitors (FTIs), R115777 (tipifarnib/Zarnestra) and BMS-214662, have undergone evaluation as cancer therapeutics in phase I and II clinical trials. R115777 has been evaluated in phase III clinical trials and shows indications for the treatment of blood and breast malignancies. Here we present crystal structures of R115777 and BMS-214662 complexed with mammalian FTase. These structures illustrate the molecular mechanism of inhibition and selectivity toward FTase over the related enzyme, protein geranylgeranyltransferase type I (GGTase-I). These results, combined with previous biochemical and structural analyses, identify features of FTase that could be exploited to modulate inhibitor potency and specificity and should aid in the continued development of FTIs as therapeutics for the treatment of cancer and parasitic infections.

PubMed: 15170324
DOI: 10.1021/bi049723b

Experimental method

X-RAY DIFFRACTION (2.6 Å)