|
|
| Line 3: |
Line 3: |
| | <StructureSection load='3mbz' size='340' side='right'caption='[[3mbz]], [[Resolution|resolution]] 2.60Å' scene=''> | | <StructureSection load='3mbz' size='340' side='right'caption='[[3mbz]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3mbz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Aciba Aciba]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3MBZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MBZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3mbz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Acinetobacter_baumannii Acinetobacter baumannii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3MBZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MBZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MXC:(2S,3R)-2-[(7-AMINOCARBONYL-2-METHANOYL-INDOLIZIN-3-YL)AMINO]-4-AMINOCARBONYLOXY-3-METHYL-3-SULFINO-BUTANOIC+ACID'>MXC</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene>, <scene name='pdbligand=MXC:(2S,3R)-2-[(7-AMINOCARBONYL-2-METHANOYL-INDOLIZIN-3-YL)AMINO]-4-AMINOCARBONYLOXY-3-METHYL-3-SULFINO-BUTANOIC+ACID'>MXC</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3g4p|3g4p]], [[3fv7|3fv7]], [[3fyz|3fyz]], [[3fzc|3fzc]]</div></td></tr>
| + | |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">bla-OXA-40, blaOXA-24, blaOXA-33, blaOXA-40, oxa-24, oxa40 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=470 ACIBA])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] </span></td></tr> | + | |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3mbz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mbz OCA], [https://pdbe.org/3mbz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mbz RCSB], [https://www.ebi.ac.uk/pdbsum/3mbz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mbz ProSAT]</span></td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3mbz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mbz OCA], [https://pdbe.org/3mbz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mbz RCSB], [https://www.ebi.ac.uk/pdbsum/3mbz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mbz ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/Q8RLA6_ACIBA Q8RLA6_ACIBA] |
| - | Class D beta-lactamases represent a growing and diverse class of penicillin-inactivating enzymes that are usually resistant to commercial beta-lactamase inhibitors. As many such enzymes are found in multi-drug resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa, novel beta-lactamase inhibitors are urgently needed. Five unique 6-alkylidene-2'-substituted penicillanic acid sulfones (1-5) were synthesized and tested against OXA-24, a clinically important beta-lactamase that inactivates carbapenems and is found in A. baumannii. Based upon the roles Tyr112 and Met223 play in the OXA-24 beta-lactamase, we also engineered two variants (Tyr112Ala and Tyr112Ala,Met223Ala) to test the hypothesis that the hydrophobic tunnel formed by these residues influences inhibitor recognition. IC(50) values against OXA-24 and two OXA-24 beta-lactamase variants ranged from 10 +/- 1 (4 vs WT) to 338 +/- 20 nM (5 vs Tyr112Ala, Met223Ala). Compound 4 possessed the lowest K(i) (500 +/- 80 nM vs WT), and 1 possessed the highest inactivation efficiency (k(inact)/K(i) = 0.21 +/- 0.02 muM(-1) s(-1)). Electrospray ionization mass spectrometry revealed a single covalent adduct, suggesting the formation of an acyl-enzyme intermediate. X-ray structures of OXA-24 complexed to four inhibitors (2.0-2.6 A) reveal the formation of stable bicyclic aromatic intermediates with their carbonyl oxygen in the oxyanion hole. These data provide the first structural evidence that 6-alkylidene-2'-substituted penicillin sulfones are effective mechanism-based inactivators of class D beta-lactamases. Their unique chemistry makes them developmental candidates. Mechanisms for class D hydrolysis and inhibition are discussed, and a pathway for the evolution of the BlaR1 sensor of Staphylococcus aureus to the class D beta-lactamases is proposed.
| + | |
| - | | + | |
| - | Design, synthesis, and crystal structures of 6-alkylidene-2'-substituted penicillanic acid sulfones as potent inhibitors of Acinetobacter baumannii OXA-24 carbapenemase.,Bou G, Santillana E, Sheri A, Beceiro A, Sampson JM, Kalp M, Bethel CR, Distler AM, Drawz SM, Pagadala SR, van den Akker F, Bonomo RA, Romero A, Buynak JD J Am Chem Soc. 2010 Sep 29;132(38):13320-31. PMID:20822105<ref>PMID:20822105</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 3mbz" style="background-color:#fffaf0;"></div>
| + | |
| | | | |
| | ==See Also== | | ==See Also== |
| | *[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | | *[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] |
| - | == References == | |
| - | <references/> | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Aciba]] | + | [[Category: Acinetobacter baumannii]] |
| - | [[Category: Beta-lactamase]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Akker, F van den]]
| + | [[Category: Sampson J]] |
| - | [[Category: Sampson, J]] | + | [[Category: Van den Akker F]] |
| - | [[Category: Beta-lactamase inhibitor]] | + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
