2y1d: Difference between revisions
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<StructureSection load='2y1d' size='340' side='right' caption='[[2y1d]], [[Resolution|resolution]] 2.05Å' scene=''> | <StructureSection load='2y1d' size='340' side='right' caption='[[2y1d]], [[Resolution|resolution]] 2.05Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2y1d]] is a 2 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=2Y1D OCA]. <br> | <table><tr><td colspan='2'>[[2y1d]] is a 2 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=2Y1D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2Y1D FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=34F:(1S)-1-(3,4-DICHLOROPHENYL)-3-[FORMYL(HYDROXY)AMINO]PROPYL}PHOSPHONIC+ACID'>34F</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>< | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=34F:(1S)-1-(3,4-DICHLOROPHENYL)-3-[FORMYL(HYDROXY)AMINO]PROPYL}PHOSPHONIC+ACID'>34F</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr> | ||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2y1c|2y1c]], [[2y1e|2y1e]], [[2y1f|2y1f]], [[2y1g|2y1g]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2y1c|2y1c]], [[2y1e|2y1e]], [[2y1f|2y1f]], [[2y1g|2y1g]]</td></tr> | ||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/ | <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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2y1d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y1d OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2y1d RCSB], [http://www.ebi.ac.uk/pdbsum/2y1d PDBsum]</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=2y1d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y1d OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2y1d RCSB], [http://www.ebi.ac.uk/pdbsum/2y1d PDBsum]</span></td></tr> | ||
<table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/A2VLK3_MYCTU A2VLK3_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).[HAMAP-Rule:MF_00183][SAAS:SAAS003821_004_013509] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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Design, Synthesis and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase.,Andaloussi M, Henriksson LM, Wieckowska A, Lindh M, Bjorkelid C, Larsson AM, Suresh S, Iyer H, Srinivasa BR, Bergfors T, Unge T, Mowbray SL, Larhed ML, Jones AT, Karlen AB J Med Chem. 2011 Jun 16. PMID:21678907<ref>PMID:21678907</ref> | Design, Synthesis and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase.,Andaloussi M, Henriksson LM, Wieckowska A, Lindh M, Bjorkelid C, Larsson AM, Suresh S, Iyer H, Srinivasa BR, Bergfors T, Unge T, Mowbray SL, Larhed ML, Jones AT, Karlen AB J Med Chem. 2011 Jun 16. PMID:21678907<ref>PMID:21678907</ref> | ||
From | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
== References == | == References == | ||
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[[Category: 1-deoxy-D-xylulose-5-phosphate reductoisomerase]] | [[Category: 1-deoxy-D-xylulose-5-phosphate reductoisomerase]] | ||
[[Category: Mycobacterium tuberculosis]] | [[Category: Mycobacterium tuberculosis]] | ||
[[Category: Bergfors, T | [[Category: Bergfors, T]] | ||
[[Category: Bjorkelid, C | [[Category: Bjorkelid, C]] | ||
[[Category: Henriksson, L M | [[Category: Henriksson, L M]] | ||
[[Category: Jones, T A | [[Category: Jones, T A]] | ||
[[Category: Larsson, A M.S | [[Category: Larsson, A M.S]] | ||
[[Category: Mowbray, S L | [[Category: Mowbray, S L]] | ||
[[Category: Unge, T | [[Category: Unge, T]] | ||
[[Category: Doxp/mep pathway]] | [[Category: Doxp/mep pathway]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
Revision as of 07:14, 25 December 2014
X-RAY STRUCTURE OF 1-DEOXY-D-XYLULOSE 5-PHOSPHATE REDUCTOISOMERASE, DXR, RV2870C, FROM MYCOBACTERIUM TUBERCULOSIS, IN COMPLEX WITH A 3,4-DICHLOROPHENYL-SUBSTITUTED FOSMIDOMYCIN ANALOGUE AND MANGANESE.X-RAY STRUCTURE OF 1-DEOXY-D-XYLULOSE 5-PHOSPHATE REDUCTOISOMERASE, DXR, RV2870C, FROM MYCOBACTERIUM TUBERCULOSIS, IN COMPLEX WITH A 3,4-DICHLOROPHENYL-SUBSTITUTED FOSMIDOMYCIN ANALOGUE AND MANGANESE.
Structural highlights
Function[A2VLK3_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).[HAMAP-Rule:MF_00183][SAAS:SAAS003821_004_013509] Publication Abstract from PubMedThe natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR) but it lacks antibacterial activity, probably because of poor uptake. alpha-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties, and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC50 = 0.15 muM on MtDXR but still lacked activity in a mycobacterial growth assay (MICs > 32 mug/ml). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite. Design, Synthesis and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase.,Andaloussi M, Henriksson LM, Wieckowska A, Lindh M, Bjorkelid C, Larsson AM, Suresh S, Iyer H, Srinivasa BR, Bergfors T, Unge T, Mowbray SL, Larhed ML, Jones AT, Karlen AB J Med Chem. 2011 Jun 16. PMID:21678907[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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