6o9w: Difference between revisions
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==Crystal structure of Staphylococcus aureus BlaR1 antibiotic-sensor domain in complex with avibactam== | ==Crystal structure of Staphylococcus aureus BlaR1 antibiotic-sensor domain in complex with avibactam== | ||
<StructureSection load='6o9w' size='340' side='right'caption='[[6o9w]]' scene=''> | <StructureSection load='6o9w' size='340' side='right'caption='[[6o9w]], [[Resolution|resolution]] 1.95Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O9W OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6O9W FirstGlance]. <br> | <table><tr><td colspan='2'>[[6o9w]] is a 2 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=6O9W OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6O9W FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6o9w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o9w OCA], [http://pdbe.org/6o9w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o9w RCSB], [http://www.ebi.ac.uk/pdbsum/6o9w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o9w ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NXL:(2S,5R)-1-FORMYL-5-[(SULFOOXY)AMINO]PIPERIDINE-2-CARBOXAMIDE'>NXL</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaR1 ([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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6o9w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o9w OCA], [http://pdbe.org/6o9w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o9w RCSB], [http://www.ebi.ac.uk/pdbsum/6o9w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o9w ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/BLAR_STAAU BLAR_STAAU]] BlaR1 is a potential penicillin-binding protein required for induction of beta-lactamase. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Methicillin-resistant Staphylococcus aureus (MRSA) infections cause significant mortality and morbidity globally. MRSA resistance to beta-lactam antibiotics is mediated by two divergons that control levels of a beta-lactamase, PC1, and a penicillin-binding protein poorly acylated by beta-lactam antibiotics, PBP2a. Expression of genes encoding these proteins is controlled by two integral membrane proteins, BlaR1 and MecR1, which both have an extracellular beta-lactam-binding sensor domain. Here, we solved the X-ray crystallographic structures of the BlaR1 and MecR1 sensor domains in complex with avibactam, a diazabicyclooctane beta-lactamase inhibitor at 1.6-2.0 A resolution. Additionally, we show that S. aureus SF8300, a clinically relevant strain from the USA300 clone of MRSA, responds to avibactam by up-regulating the expression of the blaZ and pbp2a antibiotic-resistance genes, encoding PC1 and PBP2a, respectively. The BlaR1-avibactam structure of the carbamoyl-enzyme intermediate revealed that avibactam is bound to the active-site serine in two orientations approximately 180 degrees to each other. Although a physiological role of the observed alternative pose remains to be validated, our structural results hint at the presence of a secondary sulfate-binding pocket that could be exploited in the design of future inhibitors of BlaR1/MecR1 sensor domains or the structurally similar class D beta-lactamases. The MecR1-avibactam structure adopted a singular avibactam orientation similar to one of the two states observed in the BlaR1-avibactam structure. Given avibactam up-regulates expression of blaZ and pbp2a antibiotic resistance genes, we suggest further consideration and research is needed to explore what effects administering beta-lactam-avibactam combinations have on treating MRSA infections. | |||
Structural analysis of avibactam-mediated activation of the bla and mec divergons in methicillin-resistant Staphylococcus aureus.,Alexander JAN, Radaeva M, King DT, Chambers HF, Cherkasov A, Chatterjee SS, Strynadka NCJ J Biol Chem. 2020 Aug 7;295(32):10870-10884. doi: 10.1074/jbc.RA120.013029. Epub , 2020 Jun 9. PMID:32518158<ref>PMID:32518158</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6o9w" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Alexander | [[Category: Alexander, J A.N]] | ||
[[Category: Strynadka | [[Category: Strynadka, N C.J]] | ||
[[Category: Antibiotic complex]] | |||
[[Category: Beta-lactam antibiotic sensor domain]] | |||
[[Category: Penicillin binding protein]] | |||
[[Category: Signaling protein]] | |||
