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[[Image: | ==DIHYDROFOLATE REDUCTASE OF MYCOBACTERIUM TUBERCULOSIS COMPLEXED WITH NADPH AND 4-BROMO WR99210== | ||
<StructureSection load='1dg7' size='340' side='right' caption='[[1dg7]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[1dg7]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DG7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1DG7 FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=WRB:1-[3-(4-BROMO-PHENOXY)-PROPOXY]-6,6-DIMETHYL-1.6-DIHYDRO-[1,3,5]TRIAZINE-2,4-DIAMINE'>WRB</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1df7|1df7]], [[1dg5|1dg5]], [[1dg8|1dg8]]</td></tr> | |||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><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></td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1dg7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dg7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1dg7 RCSB], [http://www.ebi.ac.uk/pdbsum/1dg7 PDBsum]</span></td></tr> | |||
<table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/dg/1dg7_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Dihydrofolate reductase (DHFR) catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate and is essential for the synthesis of thymidylate, purines and several amino acids. Inhibition of the enzyme's activity leads to arrest of DNA synthesis and cell death. The enzyme has been studied extensively as a drug target for bacterial, protozoal and fungal infections, and also for neoplastic and autoimmune diseases. Here, we report the crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis, a human pathogen responsible for the death of millions of human beings per year. Three crystal structures of ternary complexes of M. tuberculosis DHFR with NADP and different inhibitors have been determined, as well as the binary complex with NADP, with resolutions ranging from 1.7 to 2.0 A. The three DHFR inhibitors are the anticancer drug methotrexate, the antimicrobial trimethoprim and Br-WR99210, an analogue of the antimalarial agent WR99210. Structural comparison of these complexes with human dihydrofolate reductase indicates that the overall protein folds are similar, despite only 26 % sequence identity, but that the environments of both NADP and of the inhibitors contain interesting differences between the enzymes from host and pathogen. Specifically, residues Ala101 and Leu102 near the N6 of NADP are distinctly more hydrophobic in the M. tuberculosis than in the human enzyme. Another striking difference occurs in a region near atoms N1 and N8 of methotrexate, which is also near atom N1 of trimethoprim, and near the N1 and two methyl groups of Br-WR99210. A glycerol molecule binds here in a pocket of the M. tuberculosis DHFR:MTX complex, while this pocket is essentially filled with hydrophobic side-chains in the human enzyme. These differences between the enzymes from pathogen and host provide opportunities for designing new selective inhibitors of M. tuberculosis DHFR. | |||
Three-dimensional structure of M. tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs.,Li R, Sirawaraporn R, Chitnumsub P, Sirawaraporn W, Wooden J, Athappilly F, Turley S, Hol WG J Mol Biol. 2000 Jan 14;295(2):307-23. PMID:10623528<ref>PMID:10623528</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Dihydrofolate reductase|Dihydrofolate reductase]] | *[[Dihydrofolate reductase|Dihydrofolate reductase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Dihydrofolate reductase]] | [[Category: Dihydrofolate reductase]] | ||
[[Category: Mycobacterium tuberculosis]] | [[Category: Mycobacterium tuberculosis]] | ||
Revision as of 09:41, 4 September 2014
DIHYDROFOLATE REDUCTASE OF MYCOBACTERIUM TUBERCULOSIS COMPLEXED WITH NADPH AND 4-BROMO WR99210DIHYDROFOLATE REDUCTASE OF MYCOBACTERIUM TUBERCULOSIS COMPLEXED WITH NADPH AND 4-BROMO WR99210
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedDihydrofolate reductase (DHFR) catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate and is essential for the synthesis of thymidylate, purines and several amino acids. Inhibition of the enzyme's activity leads to arrest of DNA synthesis and cell death. The enzyme has been studied extensively as a drug target for bacterial, protozoal and fungal infections, and also for neoplastic and autoimmune diseases. Here, we report the crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis, a human pathogen responsible for the death of millions of human beings per year. Three crystal structures of ternary complexes of M. tuberculosis DHFR with NADP and different inhibitors have been determined, as well as the binary complex with NADP, with resolutions ranging from 1.7 to 2.0 A. The three DHFR inhibitors are the anticancer drug methotrexate, the antimicrobial trimethoprim and Br-WR99210, an analogue of the antimalarial agent WR99210. Structural comparison of these complexes with human dihydrofolate reductase indicates that the overall protein folds are similar, despite only 26 % sequence identity, but that the environments of both NADP and of the inhibitors contain interesting differences between the enzymes from host and pathogen. Specifically, residues Ala101 and Leu102 near the N6 of NADP are distinctly more hydrophobic in the M. tuberculosis than in the human enzyme. Another striking difference occurs in a region near atoms N1 and N8 of methotrexate, which is also near atom N1 of trimethoprim, and near the N1 and two methyl groups of Br-WR99210. A glycerol molecule binds here in a pocket of the M. tuberculosis DHFR:MTX complex, while this pocket is essentially filled with hydrophobic side-chains in the human enzyme. These differences between the enzymes from pathogen and host provide opportunities for designing new selective inhibitors of M. tuberculosis DHFR. Three-dimensional structure of M. tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs.,Li R, Sirawaraporn R, Chitnumsub P, Sirawaraporn W, Wooden J, Athappilly F, Turley S, Hol WG J Mol Biol. 2000 Jan 14;295(2):307-23. PMID:10623528[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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