View source for 6clv


==Staphylococcus aureus Dihydropteroate Synthase (saDHPS) F17L E208K double mutant structure==
<StructureSection load='6clv' size='340' side='right'caption='[[6clv]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6clv]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/"micrococcus_aureus"_(rosenbach_1884)_zopf_1885 "micrococcus aureus" (rosenbach 1884) zopf 1885]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CLV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CLV FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6MB:4-{[(2-AMINO-4-OXO-3,4-DIHYDROPTERIDIN-6-YL)METHYL]AMINO}-N-(3,4-DIMETHYL-1,2-OXAZOL-5-YL)BENZENE-1-SULFONAMIDE'>6MB</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">folP, dpsA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1280 "Micrococcus aureus" (Rosenbach 1884) Zopf 1885])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydropteroate_synthase Dihydropteroate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.15 2.5.1.15] </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=6clv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6clv OCA], [http://pdbe.org/6clv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6clv RCSB], [http://www.ebi.ac.uk/pdbsum/6clv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6clv ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Staphylococcal species are a leading cause of bacterial drug-resistant infections and associated mortality. One strategy to combat bacterial drug resistance is to revisit compromised targets, and to circumvent resistance mechanisms using structure-assisted drug discovery. The folate pathway is an ideal candidate for this approach. Antifolates target an essential metabolic pathway, and the necessary detailed structural information is now available for most enzymes in this pathway. Dihydropteroate synthase (DHPS) is the target of the sulfonamide class of drugs, and its well characterized mechanism facilitates detailed analyses of how drug resistance has evolved. Here, we surveyed clinical genetic sequencing data in S. aureus to distinguish natural amino acid variations in DHPS from those that are associated with sulfonamide resistance. Five mutations were identified, F17L, S18L, T51M, E208K, and KE257_dup. Their contribution to resistance and their cost to the catalytic properties of DHPS were evaluated using a combination of biochemical, biophysical and microbiological susceptibility studies. These studies show that F17L, S18L, and T51M directly lead to sulfonamide resistance while unexpectedly increasing susceptibility to trimethoprim, which targets the downstream enzyme dihydrofolate reductase. The secondary mutations E208K and KE257_dup restore trimethoprim susceptibility closer to wild-type levels while further increasing sulfonamide resistance. Structural studies reveal that these mutations appear to selectively disfavor the binding of the sulfonamides by sterically blocking an outer ring moiety that is not present in the substrate. This emphasizes that new inhibitors must be designed that strictly stay within the substrate volume in the context of the transition state.

The Structural and Functional Basis for Recurring Sulfa Drug Resistance Mutations in Staphylococcus aureus Dihydropteroate Synthase.,Griffith EC, Wallace MJ, Wu Y, Kumar G, Gajewski S, Jackson P, Phelps GA, Zheng Z, Rock CO, Lee RE, White SW Front Microbiol. 2018 Jul 17;9:1369. doi: 10.3389/fmicb.2018.01369. eCollection, 2018. PMID:30065703<ref>PMID:30065703</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6clv" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dihydropteroate synthase 3D structures|Dihydropteroate synthase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Dihydropteroate synthase]]
[[Category: Large Structures]]
[[Category: Gajewski, S]]
[[Category: Griffith, E C]]
[[Category: White, S W]]
[[Category: Wu, Y]]
[[Category: Antibiotic resistance mutation]]
[[Category: Antimicrobial protein]]
[[Category: Sulfonamide resistance]]