4s3f: Difference between revisions

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'''Unreleased structure'''
==IspG in complex with Inhibitor 8 (compound 1077)==
<StructureSection load='4s3f' size='340' side='right' caption='[[4s3f]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4s3f]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4S3F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4S3F FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=43W:BUT-3-YN-1-YL+TRIHYDROGEN+DIPHOSPHATE'>43W</scene>, <scene name='pdbligand=F3S:FE3-S4+CLUSTER'>F3S</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]], [[4s3a|4s3a]], [[4s3b|4s3b]], [[4s3c|4s3c]], [[4s3d|4s3d]], [[4s3e|4s3e]]</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=4s3f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4s3f OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4s3f RCSB], [http://www.ebi.ac.uk/pdbsum/4s3f 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.


The entry 4s3f is ON HOLD  until Paper Publication
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>


Authors: 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.
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
</div>
Description: IspG in complex with Inhibitor 8 (compound 1077)
== References ==
[[Category: Unreleased Structures]]
<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: Eppinger, J]]
[[Category: Oldfield, E]]
[[Category: Quitterer, F]]
[[Category: Quitterer, F]]
[[Category: Guerra, F]]
[[Category: Rao, G]]
[[Category: Rao, G]]
[[Category: Wang, K]]
[[Category: Wang, K]]
[[Category: O'Dowd, B]]
[[Category: Drug development]]
[[Category: Frank, A]]
[[Category: Iron-sulfur enzyme]]
[[Category: Oldfield, E]]
[[Category: Methylerythritol-phosphate pathway]]
[[Category: Bacher, A]]
[[Category: Oxidoreductase]]
[[Category: Groll, M]]
[[Category: Reaction mechanism]]
[[Category: Terpene biosynthesis]]

Revision as of 14:35, 30 April 2015

IspG in complex with Inhibitor 8 (compound 1077)IspG in complex with Inhibitor 8 (compound 1077)

Structural highlights

4s3f is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
NonStd Res:
Activity:(E)-4-hydroxy-3-methylbut-2-enyl-diphosphate synthase, with EC number 1.17.7.1
Resources:FirstGlance, OCA, RCSB, PDBsum

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 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[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ 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. Atomic-Resolution Structures of Discrete Stages on the Reaction Coordinate of the [FeS] Enzyme IspG (GcpE). J Mol Biol. 2015 Apr 11. pii: S0022-2836(15)00225-9. doi:, 10.1016/j.jmb.2015.04.002. PMID:25868383 doi:http://dx.doi.org/10.1016/j.jmb.2015.04.002

4s3f, resolution 1.70Å

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