2qk8: Difference between revisions

Revision as of 15:06, 4 May 2008

Crystal structure of the anthrax drug target, Bacillus anthracis dihydrofolate reductase

OverviewOverview

Spores of Bacillus anthracis are the infectious agent of anthrax. Current antibiotic treatments are limited due to resistance and patient age restrictions; thus, additional targets for therapeutic intervention are needed. One possible candidate is dihydrofolate reductase (DHFR), a biosynthetic enzyme necessary for anthrax pathogenicity. We determined the crystal structure of DHFR from B. anthracis (baDHFR) in complex with methotrexate (MTX; 1) at 2.4 Angstrom resolution. The structure reveals the crucial interactions required for MTX binding and a putative molecular basis for how baDHFR has natural resistance to trimethoprim (TMP; 2). The structure also allows insights for designing selective baDHFR inhibitors that will have weak affinities for the human enzyme. Additionally, we have found that 5-nitro-6-methylamino-isocytosine (MANIC; 3), which inhibits another B. anthracis folate synthesis enzyme, dihydropteroate synthase (DHPS), can also inhibit baDHFR. This provides a starting point for designing multi-target inhibitors that are less likely to induce drug resistance.

About this StructureAbout this Structure

2QK8 is a Single protein structure of sequence from Bacillus anthracis. Full crystallographic information is available from OCA.

ReferenceReference

Crystal structure of the anthrax drug target, Bacillus anthracis dihydrofolate reductase., Bennett BC, Xu H, Simmerman RF, Lee RE, Dealwis CG, J Med Chem. 2007 Sep 6;50(18):4374-81. Epub 2007 Aug 14. PMID:17696333 Page seeded by OCA on Sun May 4 15:06:22 2008

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OCA

@@ Line 1: / Line 1: @@
 [[Image:2qk8.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 2qk8 |SIZE=350|CAPTION= <scene name='initialview01'>2qk8</scene>, resolution 2.40&Aring;
+The line below this paragraph, containing "STRUCTURE_2qk8", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=MTX:METHOTREXATE'>MTX</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE= dfrA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1392 Bacillus anthracis])
+-->
-|DOMAIN=
+{{STRUCTURE_2qk8|  PDB=2qk8  |  SCENE=  }}
-|RELATEDENTRY=
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2qk8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qk8 OCA], [http://www.ebi.ac.uk/pdbsum/2qk8 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2qk8 RCSB]</span>
-}}
 '''Crystal structure of the anthrax drug target, Bacillus anthracis dihydrofolate reductase'''
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 [[Category: Simmerman, R F.]]
 [[Category: Xu, H.]]
-[[Category: methotrexate]]
+[[Category: Methotrexate]]
-[[Category: nucleotide phosphate binding]]
+[[Category: Nucleotide phosphate binding]]
-[[Category: oxidoreductase]]
+[[Category: Oxidoreductase]]
-[[Category: pseudo-rossman fold]]
+[[Category: Pseudo-rossman fold]]
-[[Category: pteridine binding]]
+[[Category: Pteridine binding]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 15:06:22 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:50:12 2008''