6o9s

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==Crystal structure of Staphylococcus aureus MecR1 antibiotic-sensor domain in complex with avibactam==
==Crystal structure of Staphylococcus aureus MecR1 antibiotic-sensor domain in complex with avibactam==
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<StructureSection load='6o9s' size='340' side='right'caption='[[6o9s]]' scene=''>
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<StructureSection load='6o9s' size='340' side='right'caption='[[6o9s]], [[Resolution|resolution]] 1.59&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O9S OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6O9S FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6o9s]] is a 1 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=6O9S OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6O9S FirstGlance]. <br>
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</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=6o9s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o9s OCA], [http://pdbe.org/6o9s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o9s RCSB], [http://www.ebi.ac.uk/pdbsum/6o9s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o9s ProSAT]</span></td></tr>
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</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>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mecR1, mecR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1280 "Micrococcus aureus" (Rosenbach 1884) Zopf 1885])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6o9s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o9s OCA], [http://pdbe.org/6o9s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o9s RCSB], [http://www.ebi.ac.uk/pdbsum/6o9s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o9s ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[[http://www.uniprot.org/uniprot/MECR_STAAU MECR_STAAU]] Penicillin-interactive protein and potential antirepressor.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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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>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6o9s" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Alexander JAN]]
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[[Category: Alexander, J A.N]]
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[[Category: Strynadka NCJ]]
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[[Category: Strynadka, N C.J]]
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[[Category: Antibiotic complex]]
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[[Category: Beta-lactam antibiotic sensor domain]]
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[[Category: Signaling protein]]

Revision as of 06:30, 7 October 2020

Crystal structure of Staphylococcus aureus MecR1 antibiotic-sensor domain in complex with avibactam

PDB ID 6o9s

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