|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Inhibitor resistant (R220A) substitution in the Mycobacterium tuberculosis beta-lactamase== | | ==Inhibitor resistant (R220A) substitution in the Mycobacterium tuberculosis beta-lactamase== |
| - | <StructureSection load='4jlf' size='340' side='right' caption='[[4jlf]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='4jlf' size='340' side='right'caption='[[4jlf]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4jlf]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JLF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JLF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4jlf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JLF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JLF FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2gdn|2gdn]]</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=4jlf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jlf OCA], [https://pdbe.org/4jlf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jlf RCSB], [https://www.ebi.ac.uk/pdbsum/4jlf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jlf ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaA, blaC, Rv2068c, MT2128, MTCY49.07c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</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 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=4jlf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jlf OCA], [http://pdbe.org/4jlf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4jlf RCSB], [http://www.ebi.ac.uk/pdbsum/4jlf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4jlf ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/BLAC_MYCTU BLAC_MYCTU] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 21: |
Line 20: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Beta-lactamase|Beta-lactamase]] | + | *[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Beta-lactamase]] | + | [[Category: Large Structures]] |
| - | [[Category: Blanchard, J]] | + | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Bonomo, R]] | + | [[Category: Blanchard J]] |
| - | [[Category: Hazra, S]] | + | [[Category: Bonomo R]] |
| - | [[Category: Kurz, S]] | + | [[Category: Hazra S]] |
| - | [[Category: Beta-lactams inactivation]]
| + | [[Category: Kurz S]] |
| - | [[Category: Drug design]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Multi drug resistance]]
| + | |
| - | [[Category: Tuberculosis]]
| + | |
| Structural highlights
Function
BLAC_MYCTU
Publication Abstract from PubMed
The current emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis calls for novel treatment strategies. Recently, BlaC, the principal beta-lactamase of Mycobacterium tuberculosis, was recognized as a potential therapeutic target. The combination of meropenem and clavulanic acid, which inhibits BlaC, was found to be effective against even extensively drug-resistant M. tuberculosis strains when tested in vitro. Yet there is significant concern that drug resistance against this combination will also emerge. To investigate the potential of BlaC to evolve variants resistant to clavulanic acid, we introduced substitutions at important amino acid residues of M. tuberculosis BlaC (R220, A244, S130, and T237). Whereas the substitutions clearly led to in vitro clavulanic acid resistance in enzymatic assays but at the expense of catalytic activity, transformation of variant BlaCs into an M. tuberculosis H37Rv background revealed that impaired inhibition of BlaC did not affect inhibition of growth in the presence of ampicillin and clavulanate. From these data we propose that resistance to beta-lactam-beta-lactamase inhibitor combinations will likely not arise from structural alteration of BlaC, therefore establishing confidence that this therapeutic modality can be part of a successful treatment regimen against M. tuberculosis.
Can inhibitor-resistant substitutions in the Mycobacterium tuberculosis beta-Lactamase BlaC lead to clavulanate resistance?: a biochemical rationale for the use of beta-lactam-beta-lactamase inhibitor combinations.,Kurz SG, Wolff KA, Hazra S, Bethel CR, Hujer AM, Smith KM, Xu Y, Tremblay LW, Blanchard JS, Nguyen L, Bonomo RA Antimicrob Agents Chemother. 2013 Dec;57(12):6085-96. doi: 10.1128/AAC.01253-13. , Epub 2013 Sep 23. PMID:24060876[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kurz SG, Wolff KA, Hazra S, Bethel CR, Hujer AM, Smith KM, Xu Y, Tremblay LW, Blanchard JS, Nguyen L, Bonomo RA. Can inhibitor-resistant substitutions in the Mycobacterium tuberculosis beta-Lactamase BlaC lead to clavulanate resistance?: a biochemical rationale for the use of beta-lactam-beta-lactamase inhibitor combinations. Antimicrob Agents Chemother. 2013 Dec;57(12):6085-96. doi: 10.1128/AAC.01253-13. , Epub 2013 Sep 23. PMID:24060876 doi:http://dx.doi.org/10.1128/AAC.01253-13
|
