3qt8: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
[[ | ==Crystal structure of mutant S192A Staphylococcus epidermidis mevalonate diphosphate decarboxylase complexed with inhibitor 6-FMVAPP== | ||
<StructureSection load='3qt8' size='340' side='right' caption='[[3qt8]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3qt8]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Staphylococcus_epidermidis Staphylococcus epidermidis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QT8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QT8 FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FM0:(3R)-3-(FLUOROMETHYL)-3-HYDROXY-5-{[(S)-HYDROXY(PHOSPHONOOXY)PHOSPHORYL]OXY}PENTANOIC+ACID'>FM0</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3qt5|3qt5]], [[3qt6|3qt6]], [[3qt7|3qt7]]</td></tr> | |||
<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mvaD ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1282 Staphylococcus epidermidis])</td></tr> | |||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Diphosphomevalonate_decarboxylase Diphosphomevalonate decarboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.33 4.1.1.33] </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=3qt8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qt8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qt8 RCSB], [http://www.ebi.ac.uk/pdbsum/3qt8 PDBsum]</span></td></tr> | |||
<table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The polyisoprenoid compound undecaprenyl phosphate is required for biosynthesis of cell wall peptidoglycans in gram-positive bacteria, including pathogenic Enterococcus, Streptococcus, and Staphylococcus spp. In these organisms, the mevalonate pathway is used to produce the precursor isoprenoid, isopentenyl 5-diphosphate. Mevalonate diphosphate decarboxylase (MDD) catalyzes formation of isopentenyl 5-diphosphate in an ATP-dependent irreversible reaction and is therefore an attractive target for inhibitor development that could lead to new antimicrobial agents. To facilitate exploration of this possibility, we report the crystal structure of Staphylococcus epidermidis MDD (1.85 A resolution) and, to the best of our knowledge, the first structures of liganded MDD. These structures include MDD bound to the mevalonate 5-diphosphate analogs diphosphoglycolyl proline (2.05 A resolution) and 6-fluoromevalonate diphosphate (FMVAPP; 2.2 A resolution). Comparison of these structures provides a physical basis for the significant differences in K(i) values observed for these inhibitors. Inspection of enzyme/inhibitor structures identified the side chain of invariant Ser(192) as making potential contributions to catalysis. Significantly, Ser --> Ala substitution of this side chain decreases k(cat) by approximately 10(3)-fold, even though binding interactions between FMVAPP and this mutant are similar to those observed with wild type MDD, as judged by the 2.1 A cocrystal structure of S192A with FMVAPP. Comparison of microbial MDD structures with those of mammalian counterparts reveals potential targets at the active site periphery that may be exploited to selectively target the microbial enzymes. These studies provide a structural basis for previous observations regarding the MDD mechanism and inform future work toward rational inhibitor design. | |||
Crystal structures of Staphylococcus epidermidis mevalonate diphosphate decarboxylase bound to inhibitory analogs reveal new insight into substrate binding and catalysis.,Barta ML, Skaff DA, McWhorter WJ, Herdendorf TJ, Miziorko HM, Geisbrecht BV J Biol Chem. 2011 Jul 8;286(27):23900-10. Epub 2011 May 11. PMID:21561869<ref>PMID:21561869</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
< | |||
[[Category: Diphosphomevalonate decarboxylase]] | [[Category: Diphosphomevalonate decarboxylase]] | ||
[[Category: Staphylococcus epidermidis]] | [[Category: Staphylococcus epidermidis]] | ||
Revision as of 07:52, 5 June 2014
Crystal structure of mutant S192A Staphylococcus epidermidis mevalonate diphosphate decarboxylase complexed with inhibitor 6-FMVAPPCrystal structure of mutant S192A Staphylococcus epidermidis mevalonate diphosphate decarboxylase complexed with inhibitor 6-FMVAPP
Structural highlights
Publication Abstract from PubMedThe polyisoprenoid compound undecaprenyl phosphate is required for biosynthesis of cell wall peptidoglycans in gram-positive bacteria, including pathogenic Enterococcus, Streptococcus, and Staphylococcus spp. In these organisms, the mevalonate pathway is used to produce the precursor isoprenoid, isopentenyl 5-diphosphate. Mevalonate diphosphate decarboxylase (MDD) catalyzes formation of isopentenyl 5-diphosphate in an ATP-dependent irreversible reaction and is therefore an attractive target for inhibitor development that could lead to new antimicrobial agents. To facilitate exploration of this possibility, we report the crystal structure of Staphylococcus epidermidis MDD (1.85 A resolution) and, to the best of our knowledge, the first structures of liganded MDD. These structures include MDD bound to the mevalonate 5-diphosphate analogs diphosphoglycolyl proline (2.05 A resolution) and 6-fluoromevalonate diphosphate (FMVAPP; 2.2 A resolution). Comparison of these structures provides a physical basis for the significant differences in K(i) values observed for these inhibitors. Inspection of enzyme/inhibitor structures identified the side chain of invariant Ser(192) as making potential contributions to catalysis. Significantly, Ser --> Ala substitution of this side chain decreases k(cat) by approximately 10(3)-fold, even though binding interactions between FMVAPP and this mutant are similar to those observed with wild type MDD, as judged by the 2.1 A cocrystal structure of S192A with FMVAPP. Comparison of microbial MDD structures with those of mammalian counterparts reveals potential targets at the active site periphery that may be exploited to selectively target the microbial enzymes. These studies provide a structural basis for previous observations regarding the MDD mechanism and inform future work toward rational inhibitor design. Crystal structures of Staphylococcus epidermidis mevalonate diphosphate decarboxylase bound to inhibitory analogs reveal new insight into substrate binding and catalysis.,Barta ML, Skaff DA, McWhorter WJ, Herdendorf TJ, Miziorko HM, Geisbrecht BV J Biol Chem. 2011 Jul 8;286(27):23900-10. Epub 2011 May 11. PMID:21561869[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||||||