1njs
From Proteopedia
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|PDB= 1njs |SIZE=350|CAPTION= <scene name='initialview01'>1njs</scene>, resolution 1.98Å | |PDB= 1njs |SIZE=350|CAPTION= <scene name='initialview01'>1njs</scene>, resolution 1.98Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= | + | |LIGAND= <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>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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] | + | |ACTIVITY= <span class='plainlinks'>[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] </span> |
|GENE= GART ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= GART ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1mej|1MEJ]], [[1men|1MEN]], [[1meo|1MEO]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1njs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1njs OCA], [http://www.ebi.ac.uk/pdbsum/1njs PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1njs RCSB]</span> | ||
}} | }} | ||
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[[Category: Wilson, I A.]] | [[Category: Wilson, I A.]] | ||
[[Category: Zhang, Y.]] | [[Category: Zhang, Y.]] | ||
| - | [[Category: KEU]] | ||
| - | [[Category: PO4]] | ||
[[Category: protein-cofactor analogue complex]] | [[Category: protein-cofactor analogue complex]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 22:31:22 2008'' |
Revision as of 19:31, 30 March 2008
| |||||||
| , resolution 1.98Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Gene: | GART (Homo sapiens) | ||||||
| Activity: | Phosphoribosylglycinamide formyltransferase, with EC number 2.1.2.2 | ||||||
| Related: | 1MEJ, 1MEN, 1MEO
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| 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
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