4s3a: Difference between revisions
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''' | ==IspG in complex with Intermediate I== | ||
<StructureSection load='4s3a' size='340' side='right' caption='[[4s3a]], [[Resolution|resolution]] 1.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4s3a]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4S3A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4S3A FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=43Q:(3S)-1,3-DIHYDROXY-4-{[(S)-HYDROXY(PHOSPHONOOXY)PHOSPHORYL]OXY}-2-METHYLBUT-2-YLIUM,+CARBOKATION+INTERMEDIATE'>43Q</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SF4:IRON/SULFUR+CLUSTER'>SF4</scene></td></tr> | |||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4g9p|4g9p]], [[2y0f|2y0f]], [[3noy|3noy]], [[4s38|4s38]], [[4s39|4s39]], [[4s3b|4s3b]], [[4s3c|4s3c]], [[4s3d|4s3d]], [[4s3e|4s3e]], [[4s3f|4s3f]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/(E)-4-hydroxy-3-methylbut-2-enyl-diphosphate_synthase (E)-4-hydroxy-3-methylbut-2-enyl-diphosphate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.17.7.1 1.17.7.1] </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=4s3a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4s3a OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4s3a RCSB], [http://www.ebi.ac.uk/pdbsum/4s3a PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/ISPG_THET8 ISPG_THET8]] Converts 2C-methyl-D-erythritol 2,4-cyclodiphosphate (ME-2,4cPP) into 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
IspG is the penultimate enzyme in non-mevalonate biosynthesis of the universal terpene building blocks isopentenyl diphosphate and dimethylallyl diphosphate. Its mechanism of action has been the subject of numerous studies but remained unresolved due to difficulties in identifying distinct reaction intermediates. Using a moderate reducing agent and an epoxide substrate analogue, we were now able to trap and crystallographically characterize various stages in the IspG-catalyzed conversion of 2-C-methyl-d-erythritol-2,4-cyclo-diphosphate into (E)-1-hydroxy-2-methylbut-2-enyl-4-diphosphate. In addition, the enzyme's structure was determined in complex with several inhibitors. These results, combined with recent electron paramagnetic resonance data, allowed us to deduce a detailed and complete IspG catalytic mechanism, which describes all stages from initial ring opening to formation of (E)-1-hydroxy-2-methylbut-2-enyl-4-diphosphate via discrete radical and carbanion intermediates. The data presented in this article provide a guide for the design of selective drugs against many prokaryotic and eukaryotic pathogens to which the non-mevalonate pathway is essential for survival and virulence. | |||
Atomic-Resolution Structures of Discrete Stages on the Reaction Coordinate of the [FeS] Enzyme IspG (GcpE).,Quitterer F, Frank A, Wang K, Rao G, O'Dowd B, Li J, Guerra F, Abdel-Azeim S, Bacher A, Eppinger J, Oldfield E, Groll M J Mol Biol. 2015 Apr 11. pii: S0022-2836(15)00225-9. doi:, 10.1016/j.jmb.2015.04.002. PMID:25868383<ref>PMID:25868383</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Abdel-Azeim, S]] | [[Category: Abdel-Azeim, S]] | ||
[[Category: Bacher, A]] | |||
[[Category: Dowd, B O]] | |||
[[Category: Eppinger, J]] | |||
[[Category: Frank, A]] | |||
[[Category: Groll, M]] | |||
[[Category: Guerra, F]] | |||
[[Category: Li, J]] | [[Category: Li, J]] | ||
[[Category: | [[Category: Oldfield, E]] | ||
[[Category: Quitterer, F]] | [[Category: Quitterer, F]] | ||
[[Category: Rao, G]] | [[Category: Rao, G]] | ||
[[Category: Wang, K]] | [[Category: Wang, K]] | ||
[[Category: | [[Category: Drug development]] | ||
[[Category: | [[Category: Iron-sulfur enzyme]] | ||
[[Category: | [[Category: Methylerythritol-phosphate pathway]] | ||
[[Category: | [[Category: Oxidoreductase]] | ||
[[Category: | [[Category: Reaction mechanism]] | ||
[[Category: Terpene biosynthesis]] | |||
Revision as of 15:50, 6 May 2015
IspG in complex with Intermediate IIspG in complex with Intermediate I
Structural highlights
Function[ISPG_THET8] Converts 2C-methyl-D-erythritol 2,4-cyclodiphosphate (ME-2,4cPP) into 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate. Publication Abstract from PubMedIspG is the penultimate enzyme in non-mevalonate biosynthesis of the universal terpene building blocks isopentenyl diphosphate and dimethylallyl diphosphate. Its mechanism of action has been the subject of numerous studies but remained unresolved due to difficulties in identifying distinct reaction intermediates. Using a moderate reducing agent and an epoxide substrate analogue, we were now able to trap and crystallographically characterize various stages in the IspG-catalyzed conversion of 2-C-methyl-d-erythritol-2,4-cyclo-diphosphate into (E)-1-hydroxy-2-methylbut-2-enyl-4-diphosphate. In addition, the enzyme's structure was determined in complex with several inhibitors. These results, combined with recent electron paramagnetic resonance data, allowed us to deduce a detailed and complete IspG catalytic mechanism, which describes all stages from initial ring opening to formation of (E)-1-hydroxy-2-methylbut-2-enyl-4-diphosphate via discrete radical and carbanion intermediates. The data presented in this article provide a guide for the design of selective drugs against many prokaryotic and eukaryotic pathogens to which the non-mevalonate pathway is essential for survival and virulence. Atomic-Resolution Structures of Discrete Stages on the Reaction Coordinate of the [FeS] Enzyme IspG (GcpE).,Quitterer F, Frank A, Wang K, Rao G, O'Dowd B, Li J, Guerra F, Abdel-Azeim S, Bacher A, Eppinger J, Oldfield E, Groll M J Mol Biol. 2015 Apr 11. pii: S0022-2836(15)00225-9. doi:, 10.1016/j.jmb.2015.04.002. PMID:25868383[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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