View source for 5jnl


==Structure of Plasmodium falciparum DXR in complex with a beta-substituted fosmidomycin analogue, LC54 and manganese==
<StructureSection load='5jnl' size='340' side='right'caption='[[5jnl]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5jnl]] 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=5JNL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JNL 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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=L54:{(2R)-2-{2-[HYDROXY(METHYL)AMINO]-2-OXOETHYL}-5-[4-(TRIFLUOROMETHYL)PHENYL]PENTYL}PHOSPHONIC+ACID'>L54</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</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=5jnl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jnl OCA], [https://pdbe.org/5jnl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jnl RCSB], [https://www.ebi.ac.uk/pdbsum/5jnl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jnl 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).
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the beta-position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P. falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X-ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active-site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta-substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency.

Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with beta-Arylpropyl Analogues of Fosmidomycin.,Sooriyaarachchi S, Chofor R, Risseeuw MD, Bergfors T, Pouyez J, Dowd CS, Maes L, Wouters J, Jones TA, Van Calenbergh S, Mowbray SL ChemMedChem. 2016 Aug 3. doi: 10.1002/cmdc.201600249. PMID:27487410<ref>PMID:27487410</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 5jnl" 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]]