View source for 4y67


==Structure of Plasmodium falciparum DXR in complex with a beta-substituted fosmidomycin analogue, RC176, and manganese==
<StructureSection load='4y67' size='340' side='right'caption='[[4y67]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4y67]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y67 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Y67 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]] 1.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=RC5:[(2R)-2-{2-[HYDROXY(METHYL)AMINO]-2-OXOETHYL}-5-PHENYLPENTYL]PHOSPHONIC+ACID'>RC5</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=4y67 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y67 OCA], [https://pdbe.org/4y67 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4y67 RCSB], [https://www.ebi.ac.uk/pdbsum/4y67 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4y67 ProSAT]</span></td></tr>
</table>
== Function ==
[https://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).
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== 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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 4y67" style="background-color:#fffaf0;"></div>

==See Also==
*[[DXP reductoisomerase 3D Structures|DXP reductoisomerase 3D Structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Plasmodium falciparum 3D7]]
[[Category: Bergfors T]]
[[Category: Jones TA]]
[[Category: Mowbray SL]]
[[Category: Sooriyaarachchi S]]