4y6p: Difference between revisions
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''' | ==Structure of Plasmodium falciparum DXR in complex with a beta-substituted fosmidomycin analogue, RC177, and manganese== | ||
<StructureSection load='4y6p' size='340' side='right' caption='[[4y6p]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4y6p]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y6P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y6P FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=R77:[(2R)-2-{2-[HYDROXY(METHYL)AMINO]-2-OXOETHYL}-6-PHENYLHEXYL]PHOSPHONIC+ACID'>R77</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4y67|4y67]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/1-deoxy-D-xylulose-5-phosphate_reductoisomerase 1-deoxy-D-xylulose-5-phosphate reductoisomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.267 1.1.1.267] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4y6p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y6p OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4y6p RCSB], [http://www.ebi.ac.uk/pdbsum/4y6p PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/DXR_PLAF7 DXR_PLAF7]] Catalyzes the NADP-dependent rearrangement and reduction of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol 4-phosphate (MEP). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the beta-position of the hydroxamate analogue of 2. While direct addition of a beta-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the "longer" compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate's methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth. | |||
Synthesis and Bioactivity of beta-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase.,Chofor R, Sooriyaarachchi S, Risseeuw MD, Bergfors T, Pouyez J, Johny C, Haymond A, Everaert A, Dowd CS, Maes L, Coenye T, Alex A, Couch RD, Jones TA, Wouters J, Mowbray SL, Van Calenbergh S J Med Chem. 2015 Mar 31. PMID:25781377<ref>PMID:25781377</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: 1-deoxy-D-xylulose-5-phosphate reductoisomerase]] | |||
[[Category: Bergfors, T]] | [[Category: Bergfors, T]] | ||
[[Category: Jones, T | [[Category: Jones, T A]] | ||
[[Category: Mowbray, S | [[Category: Mowbray, S L]] | ||
[[Category: Sooriyaarachchi, S]] | [[Category: Sooriyaarachchi, S]] | ||
[[Category: Enzyme-inhibitor complex]] | |||
[[Category: Isoprenoid biosynthesis]] | |||
[[Category: Mep pathway]] | |||
[[Category: Oxidoreductase]] | |||
Revision as of 16:10, 1 April 2015
Structure of Plasmodium falciparum DXR in complex with a beta-substituted fosmidomycin analogue, RC177, and manganeseStructure of Plasmodium falciparum DXR in complex with a beta-substituted fosmidomycin analogue, RC177, and manganese
Structural highlights
Function[DXR_PLAF7] Catalyzes the NADP-dependent rearrangement and reduction of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol 4-phosphate (MEP). Publication Abstract from PubMedBlocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the beta-position of the hydroxamate analogue of 2. While direct addition of a beta-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the "longer" compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate's methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth. Synthesis and Bioactivity of beta-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase.,Chofor R, Sooriyaarachchi S, Risseeuw MD, Bergfors T, Pouyez J, Johny C, Haymond A, Everaert A, Dowd CS, Maes L, Coenye T, Alex A, Couch RD, Jones TA, Wouters J, Mowbray SL, Van Calenbergh S J Med Chem. 2015 Mar 31. PMID:25781377[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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