3c8n: Difference between revisions
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==Crystal structure of apo-FGD1 from Mycobacterium tuberculosis== | ==Crystal structure of apo-FGD1 from Mycobacterium tuberculosis== | ||
<StructureSection load='3c8n' size='340' side='right' caption='[[3c8n]], [[Resolution|resolution]] 1.90Å' scene=''> | <StructureSection load='3c8n' size='340' side='right'caption='[[3c8n]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3c8n]] is a 4 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3c8n]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3C8N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3C8N FirstGlance]. <br> | ||
</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3b4y|3b4y]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3b4y|3b4y]]</div></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">fgd1, fgd, MT0420, Rv0407 ([ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">fgd1, fgd, MT0420, Rv0407 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3c8n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3c8n OCA], [https://pdbe.org/3c8n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3c8n RCSB], [https://www.ebi.ac.uk/pdbsum/3c8n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3c8n ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[ | [[https://www.uniprot.org/uniprot/FGD_MYCTU FGD_MYCTU]] Catalyzes the coenzyme F420-dependent oxidation of glucose 6-phosphate to 6-phosphogluconolactone. Is essential for the bioreductive activation of the prodrug PA-824 (nitroimidazo-oxazine) developed for anti-tuberculosis therapy against both replicating and persistent bacteria. It does not interact directly with PA-824 but, rather, provides reduced F420 to an accessory protein (Rv3547), which in turn activates PA-824. Also probably has a role in resistance to oxidative stress, via its consumption of G6P that serves as a source of reducing power to combat oxidative stress in mycobacteria.<ref>PMID:10879539</ref> <ref>PMID:18434308</ref> | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Myctu]] | [[Category: Myctu]] | ||
[[Category: Baker, E N]] | [[Category: Baker, E N]] | ||
Revision as of 22:07, 20 October 2021
Crystal structure of apo-FGD1 from Mycobacterium tuberculosisCrystal structure of apo-FGD1 from Mycobacterium tuberculosis
Structural highlights
Function[FGD_MYCTU] Catalyzes the coenzyme F420-dependent oxidation of glucose 6-phosphate to 6-phosphogluconolactone. Is essential for the bioreductive activation of the prodrug PA-824 (nitroimidazo-oxazine) developed for anti-tuberculosis therapy against both replicating and persistent bacteria. It does not interact directly with PA-824 but, rather, provides reduced F420 to an accessory protein (Rv3547), which in turn activates PA-824. Also probably has a role in resistance to oxidative stress, via its consumption of G6P that serves as a source of reducing power to combat oxidative stress in mycobacteria.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe modified flavin coenzyme F(420) is found in a restricted number of microorganisms. It is widely distributed in mycobacteria, however, where it is important in energy metabolism, and in Mycobacterium tuberculosis (Mtb) is implicated in redox processes related to non-replicating persistence. In Mtb, the F(420)-dependent glucose-6-phosphate dehydrogenase FGD1 provides reduced F(420) for the in vivo activation of the nitroimidazopyran prodrug PA-824, currently being developed for anti-tuberculosis therapy against both replicating and persistent bacteria. The structure of M. tuberculosis FGD1 has been determined by x-ray crystallography both in its apo state and in complex with F(420) and citrate at resolutions of 1.90 and 1.95 A(,) respectively. The structure reveals a highly specific F(420) binding mode, which is shared with several other F(420)-dependent enzymes. Citrate occupies the substrate binding pocket adjacent to F(420) and is shown to be a competitive inhibitor (IC(50) 43 microm). Modeling of the binding of the glucose 6-phosphate (G6P) substrate identifies a positively charged phosphate binding pocket and shows that G6P, like citrate, packs against the isoalloxazine moiety of F(420) and helps promote a butterfly bend conformation that facilitates F(420) reduction and catalysis. Crystal structures of F420-dependent glucose-6-phosphate dehydrogenase FGD1 involved in the activation of the anti-tuberculosis drug candidate PA-824 reveal the basis of coenzyme and substrate binding.,Bashiri G, Squire CJ, Moreland NJ, Baker EN J Biol Chem. 2008 Jun 20;283(25):17531-41. Epub 2008 Apr 22. PMID:18434308[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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