Farnesyltransferases structure

Dunten, P., Kammlott, U., Crowther, R., Weber, D., Palermo, R., and Birktoft, J. (1998). Protein farnesyltransferase structure and imphcations for substrate binding. Biochemistry 37 7907-7912. 

Lane KT, Beese LS (2006) Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I. J Lipid Res 47 681-699... 

Park HW et al (1997) Crystal structure of protein farnesyltransferase at 2.25 angstrom resolution. Science 275(5307) 1800-1804... 

Farnesyltransferase inhibitor, IC5Q 25 pM from structure-based virtual screening... 

Long, S.B., Casey, P.J., and Beese, L.S. (1998). Cocrystal structure of protein farnesyltransferase complexed with a farnesyl diphosphate substrate. Biochemistry 37 9612-9618. 

Reid, T.S., and Beese, L.S. (2004). 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. 

This technique has been successfully applied in those biological targets where the key structural amino acids of the native peptide for peptide recognition are known. Miscellaneous examples are found in glycoprotein Gbllb/IIIa inhibitors (33)that mimic the RGD sequence (64) or in Ras-farnesyltransferase inhibitors (34) that mimic the CAAX sequence (Fig. 15.15) (65). 

Local pharmacophore models have also been generated around narrow structural series such as the sertindole analogues [30], For example, publications containing [3H]-dofetilide binding data for the 5ffT2A class of molecules [44,45], and 3-aminopyrrolidinone farnesyltransferase inhibitors [46], have been used to produce individual pharmacophores that were ultimately combined to suggest common areas of positive ionizable features and hydropho-bicity from aromatic rings [31,47],... 

Polley, M.J., Winkler, D.A. and Burden, F.R. (2004) Broad-based quantitative structure-activity relationship modeling of potency and selectivity of farnesyltransferase inhibitors using a Bayesian regularized neural network. J. Mod. Chem., 47, 6230-6238. 

Roquefortine C was often accompanied by a structurally related mycotoxin isofumigaclavine A (12-98). P. roqueforti molds may occasionally produce patulin, citrinin (12-99), penicillic acid (12-100), the so-called PR-toxin (12-101) and certain other toxins that have been implicated in incidents of mycotoxicoses. However, PR toxin is not stable in cheese and breaks down to the less toxic PR imine (12-101). Other secondary metabolites ofP. roqueforti found in blue cheeses are andrastins A-D with skeletons of ent-5a,lA -androstane. In European blue cheeses, the content of andrastin A (12-102) ranged from 0.1 to 3.7 mg/kg and contents of andrastins B, C and D were on average five times lower. The most significant biological activity of adrastins is the ability to inhibit the enzyme farnesyltransferase, an enzyme that catalyses the transfer of farnesyl residue from farnesyl diphosphate to proteins. It is a part of the apparatus carrying post-translational modification of proteins in... 

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