1njs
From Proteopedia
| Line 1: | Line 1: | ||
| - | [[Image:1njs.gif|left|200px]] | + | [[Image:1njs.gif|left|200px]] |
| - | + | ||
| - | '''human GAR Tfase in complex with hydrolyzed form of 10-trifluoroacetyl-5,10-dideaza-acyclic-5,6,7,8-tetrahydrofolic acid''' | + | {{Structure |
| + | |PDB= 1njs |SIZE=350|CAPTION= <scene name='initialview01'>1njs</scene>, resolution 1.98Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene> and <scene name='pdbligand=KEU:N-{4-[(1R)-4-[(2R,4R,5S)-2,4-DIAMINO-6-OXOHEXAHYDROPYRIMIDIN-5-YL]-1-(2,2,2-TRIFLUORO-1,1-DIHYDROXYETHYL)BUTYL]BENZOYL}-D-GLUTAMIC ACID'>KEU</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/Phosphoribosylglycinamide_formyltransferase Phosphoribosylglycinamide formyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.2.2 2.1.2.2] | ||
| + | |GENE= GART ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | }} | ||
| + | |||
| + | '''human GAR Tfase in complex with hydrolyzed form of 10-trifluoroacetyl-5,10-dideaza-acyclic-5,6,7,8-tetrahydrofolic acid''' | ||
| + | |||
==Overview== | ==Overview== | ||
| Line 7: | Line 16: | ||
==About this Structure== | ==About this Structure== | ||
| - | 1NJS is a [ | + | 1NJS is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NJS OCA]. |
==Reference== | ==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:[http:// | + | 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:[http://www.ncbi.nlm.nih.gov/pubmed/12755606 12755606] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Phosphoribosylglycinamide formyltransferase]] | [[Category: Phosphoribosylglycinamide formyltransferase]] | ||
| Line 29: | Line 38: | ||
[[Category: protein-cofactor analogue complex]] | [[Category: protein-cofactor analogue complex]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 12:57:48 2008'' |
Revision as of 10:57, 20 March 2008
| |||||||
| , resolution 1.98Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | and | ||||||
| Gene: | GART (Homo sapiens) | ||||||
| Activity: | Phosphoribosylglycinamide formyltransferase, with EC number 2.1.2.2 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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. 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 Thu Mar 20 12:57:48 2008
Categories: Homo sapiens | Phosphoribosylglycinamide formyltransferase | Single protein | Benkovic, S J. | Boger, D L. | Desharnais, J. | Gooljarsingh, L T. | Hedrick, M P. | Li, C. | Marsilje, T H. | Olson, A J. | Tavassoli, A. | Wilson, I A. | Zhang, Y. | KEU | PO4 | Protein-cofactor analogue complex
