3fv7: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3fv7]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Acinetobacter_baumannii Acinetobacter baumannii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FV7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3FV7 FirstGlance]. <br> | <table><tr><td colspan='2'>[[3fv7]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Acinetobacter_baumannii Acinetobacter baumannii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FV7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3FV7 FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MXS:(2S)-2-[[2-METHANOYL-7-(METHOXYCARBONYLAMINO)INDOLIZIN-3-YL]AMINO]-3-METHYL-3-SULFINO-BUTANOIC+ACID'>MXS</scene>< | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MXS:(2S)-2-[[2-METHANOYL-7-(METHOXYCARBONYLAMINO)INDOLIZIN-3-YL]AMINO]-3-METHYL-3-SULFINO-BUTANOIC+ACID'>MXS</scene></td></tr> | ||
<tr><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='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><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaOXA-33, bla-OXA-40, oxa-24, oxa40 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=470 Acinetobacter baumannii])</td></tr> | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaOXA-33, bla-OXA-40, oxa-24, oxa40 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=470 Acinetobacter baumannii])</td></tr> | ||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] </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=3fv7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fv7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3fv7 RCSB], [http://www.ebi.ac.uk/pdbsum/3fv7 PDBsum]</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=3fv7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fv7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3fv7 RCSB], [http://www.ebi.ac.uk/pdbsum/3fv7 PDBsum]</span></td></tr> | ||
<table> | </table> | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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[[Category: Acinetobacter baumannii]] | [[Category: Acinetobacter baumannii]] | ||
[[Category: Beta-lactamase]] | [[Category: Beta-lactamase]] | ||
[[Category: Akker, F Van den | [[Category: Akker, F Van den]] | ||
[[Category: Beceiro, A | [[Category: Beceiro, A]] | ||
[[Category: Bethel, C R | [[Category: Bethel, C R]] | ||
[[Category: Bonomo, R A | [[Category: Bonomo, R A]] | ||
[[Category: Bou, G | [[Category: Bou, G]] | ||
[[Category: Buynak, J D | [[Category: Buynak, J D]] | ||
[[Category: Distler, A M | [[Category: Distler, A M]] | ||
[[Category: Drawz, S M | [[Category: Drawz, S M]] | ||
[[Category: Kalp, M | [[Category: Kalp, M]] | ||
[[Category: Pagadala, S R | [[Category: Pagadala, S R]] | ||
[[Category: Romero, A | [[Category: Romero, A]] | ||
[[Category: Sampson, J M | [[Category: Sampson, J M]] | ||
[[Category: Santillana, E | [[Category: Santillana, E]] | ||
[[Category: Sheri, A | [[Category: Sheri, A]] | ||
[[Category: B-lactamase]] | [[Category: B-lactamase]] | ||
[[Category: Carbapenem]] | [[Category: Carbapenem]] | ||
Revision as of 14:41, 20 January 2015
OXA-24 beta-lactamase complex with SA4-44 inhibitorOXA-24 beta-lactamase complex with SA4-44 inhibitor
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedClass 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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