3zhy: Difference between revisions
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The | ==Structure of Mycobacterium tuberculosis DXR in complex with a di- substituted fosmidomycin analogue== | ||
<StructureSection load='3zhy' size='340' side='right'caption='[[3zhy]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3zhy]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZHY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ZHY FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FM6:[(1S)-1-(3,4-DICHLOROPHENYL)-3-[OXIDANYL(PHENYLCARBONYL)AMINO]PROPYL]PHOSPHONIC+ACID'>FM6</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3zhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zhy OCA], [https://pdbe.org/3zhy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3zhy RCSB], [https://www.ebi.ac.uk/pdbsum/3zhy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3zhy ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/DXR_MYCTU DXR_MYCTU] Catalyzes the NADP-dependent rearrangement and reduction of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol 4-phosphate (MEP) (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway, producing the essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Calpha and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the polar and cramped (and so not easily druggable) substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC50 of 40 nM. | |||
DXR inhibition by potent mono- and disubstituted fosmidomycin analogues.,Jansson AM, Wieckowska A, Bjorkelid C, Yahiaoui S, Sooriyaarachchi S, Lindh M, Bergfors T, Dharavath S, Desroses M, Suresh S, Andaloussi M, Nikhil R, Sreevalli S, Srinivasa BR, Larhed M, Jones TA, Karlen A, Mowbray SL J Med Chem. 2013 Aug 8;56(15):6190-9. doi: 10.1021/jm4006498. Epub 2013 Jul 17. PMID:23819803<ref>PMID:23819803</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3zhy" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[DXP reductoisomerase|DXP reductoisomerase]] | |||
*[[DXP reductoisomerase 3D Structures|DXP reductoisomerase 3D Structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycobacterium tuberculosis H37Rv]] | |||
[[Category: Bergfors T]] | |||
[[Category: Bjorkelid C]] | |||
[[Category: Jansson AM]] | |||
[[Category: Jones TA]] | |||
[[Category: Mowbray SL]] | |||
[[Category: Unge T]] | |||
Latest revision as of 13:39, 9 May 2024
Structure of Mycobacterium tuberculosis DXR in complex with a di- substituted fosmidomycin analogueStructure of Mycobacterium tuberculosis DXR in complex with a di- substituted fosmidomycin analogue
Structural highlights
FunctionDXR_MYCTU Catalyzes the NADP-dependent rearrangement and reduction of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol 4-phosphate (MEP) (By similarity). Publication Abstract from PubMedThe antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway, producing the essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Calpha and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the polar and cramped (and so not easily druggable) substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC50 of 40 nM. DXR inhibition by potent mono- and disubstituted fosmidomycin analogues.,Jansson AM, Wieckowska A, Bjorkelid C, Yahiaoui S, Sooriyaarachchi S, Lindh M, Bergfors T, Dharavath S, Desroses M, Suresh S, Andaloussi M, Nikhil R, Sreevalli S, Srinivasa BR, Larhed M, Jones TA, Karlen A, Mowbray SL J Med Chem. 2013 Aug 8;56(15):6190-9. doi: 10.1021/jm4006498. Epub 2013 Jul 17. PMID:23819803[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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