1njs

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spinqualitylabelsall models 1njs, resolution 1.98Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

human GAR Tfase in complex with hydrolyzed form of 10-trifluoroacetyl-5,10-dideaza-acyclic-5,6,7,8-tetrahydrofolic acid

Overview

Glycinamide ribonucleotide transformylase (GAR Tfase) has been the target, of anti-neoplastic intervention for almost two decades. Here, we use a, structure-based approach to design a novel folate analogue, 10-(trifluoroacetyl)-5,10-dideazaacyclic-5,6,7,8-tetrahydrofolic acid, (10-CF(3)CO-DDACTHF, 1), which specifically inhibits recombinant human GAR, Tfase (K(i) = 15 nM), but is inactive (K(i) > 100 microM) against other, folate-dependent enzymes that have been examined. Moreover, compound 1 is, a potent inhibitor of tumor cell proliferation (IC(50) = 16 nM, CCRF-CEM), which represents a 10-fold improvement over Lometrexol, a GAR Tfase, inhibitor that has been in clinical trials. Thus, this folate analogue 1, is among the most potent and selective inhibitors known toward GAR Tfase., Contributing to its efficacious activity, compound 1 is effectively, transported into the cell by the reduced folate carrier and, intracellularly sequestered by polyglutamation. The crystal structure of, human GAR Tfase with folate analogue 1 at 1.98 A resolution represents the, first structure of any GAR Tfase to be determined with a cofactor or, cofactor analogue without the presence of substrate. The folate-binding, loop of residues 141-146, which is highly flexible in both Escherichia, coli and unliganded human GAR Tfase structures, becomes highly ordered, upon binding 1 in the folate-binding site. Computational docking of the, natural cofactor into this and other apo or complexed structures provides, a rational basis for modeling how the natural cofactor, 10-formyltetrahydrofolic acid interacts with GAR Tfase, and suggests that, this folate analogue-bound conformation represents the best template to, date for inhibitor design.

About this Structure

1NJS is a Single protein structure of sequence from Homo sapiens with PO4 and KEU as ligands. Active as Phosphoribosylglycinamide formyltransferase, with EC number 2.1.2.2 Full crystallographic information is available from OCA.

Reference

Rational design, synthesis, evaluation, and crystal structure of a potent inhibitor of human GAR Tfase: 10-(trifluoroacetyl)-5,10-dideazaacyclic-5,6,7,8-tetrahydrofolic acid., Zhang Y, Desharnais J, Marsilje TH, Li C, Hedrick MP, Gooljarsingh LT, Tavassoli A, Benkovic SJ, Olson AJ, Boger DL, Wilson IA, Biochemistry. 2003 May 27;42(20):6043-56. PMID:12755606

Page seeded by OCA on Mon Nov 12 18:21:58 2007