3m6h: Difference between revisions
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==Crystal Structure of Post-isomerized Ertapenem Covalent Adduct with TB B-lactamase== | ==Crystal Structure of Post-isomerized Ertapenem Covalent Adduct with TB B-lactamase== | ||
<StructureSection load='3m6h' size='340' side='right' caption='[[3m6h]], [[Resolution|resolution]] 1.99Å' scene=''> | <StructureSection load='3m6h' size='340' side='right' caption='[[3m6h]], [[Resolution|resolution]] 1.99Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3m6h]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[3m6h]] 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=3M6H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3M6H FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2RG:(2S,3R,4S)-4-({(3S,5S)-5-[(3-CARBOXYPHENYL)CARBAMOYL]PYRROLIDIN-3-YL}SULFANYL)-2-[(1S,2R)-1-FORMYL-2-HYDROXYPROPYL]-3-METHYL-3,4-DIHYDRO-2H-PYRROLE-5-CARBOXYLIC+ACID'>2RG</scene>, <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"><scene name='pdbligand=2RG:(2S,3R,4S)-4-({(3S,5S)-5-[(3-CARBOXYPHENYL)CARBAMOYL]PYRROLIDIN-3-YL}SULFANYL)-2-[(1S,2R)-1-FORMYL-2-HYDROXYPROPYL]-3-METHYL-3,4-DIHYDRO-2H-PYRROLE-5-CARBOXYLIC+ACID'>2RG</scene>, <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">[[3m6b|3m6b]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3m6b|3m6b]]</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 | <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='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=3m6h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3m6h OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3m6h RCSB], [http://www.ebi.ac.uk/pdbsum/3m6h 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=3m6h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3m6h OCA], [http://pdbe.org/3m6h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3m6h RCSB], [http://www.ebi.ac.uk/pdbsum/3m6h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3m6h ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
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<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
</jmolCheckbox> | </jmolCheckbox> | ||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/ | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3m6h ConSurf]. | ||
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 3m6h" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Beta-lactamase]] | [[Category: Beta-lactamase]] | ||
[[Category: Tremblay, L W]] | [[Category: Tremblay, L W]] | ||
[[Category: Alpha-beta structure]] | [[Category: Alpha-beta structure]] | ||
Revision as of 07:01, 10 December 2016
Crystal Structure of Post-isomerized Ertapenem Covalent Adduct with TB B-lactamaseCrystal Structure of Post-isomerized Ertapenem Covalent Adduct with TB B-lactamase
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 PubMedDespite the enormous success of beta-lactams as broad-spectrum antibacterials, they have never been widely used for the treatment of tuberculosis (TB) due to intrinsic resistance that is caused by the presence of a chromosomally encoded gene (blaC) in Mycobacterium tuberculosis. Our previous studies of TB BlaC revealed that this enzyme is an extremely broad-spectrum beta-lactamase hydrolyzing all beta-lactam classes. Carbapenems are slow substrates that acylate the enzyme but are only slowly deacylated and can therefore act also as potent inhibitors of BlaC. We conducted the in vitro characterization of doripenem and ertapenem with BlaC. A steady-state kinetic burst was observed with both compounds with magnitudes proportional to the concentration of BlaC used. The results provide apparent K(m) and k(cat) values of 0.18 muM and 0.016 min(-1) for doripenem and 0.18 muM and 0.017 min(-1) for ertapenem, respectively. FTICR mass spectrometry demonstrated that the doripenem and ertapenem acyl-enzyme complexes remain stable over a time period of 90 min. The BlaC-doripenem covalent complex obtained after a 90 min soak was determined to 2.2 A, while the BlaC-ertapenem complex obtained after a 90 min soak was determined to 2.0 A. The 1.3 A diffraction data from a 10 min ertapenem-soaked crystal revealed an isomerization occurring in the BlaC-ertapenem adduct in which the original Delta(2)-pyrroline ring was tautomerized to generate the Delta(1)-pyrroline ring. The isomerization leads to the flipping of the carbapenem hydroxyethyl group to hydrogen bond to carboxyl O2 of Glu166. The hydroxyethyl flip results in both the decreased basicity of Glu166 and a significant increase in the distance between carboxyl O2 of Glu166 and the catalytic water molecule, slowing hydrolysis. Biochemical and Structural Characterization of Mycobacterium tuberculosis beta-Lactamase with the Carbapenems Ertapenem and Doripenem.,Tremblay LW, Fan F, Blanchard JS Biochemistry. 2010 Apr 7. PMID:20353175[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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