6h2c: Difference between revisions
New page: '''Unreleased structure''' The entry 6h2c is ON HOLD Authors: Tassoni, R., Pannu, N.S., Ubbink, M. Description: Structure of BlaC from Mycobacterium tuberculosis bound to the trans-ena... |
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The | ==Structure of BlaC from Mycobacterium tuberculosis bound to the trans-enamine adduct derived from clavulanic acid.== | ||
<StructureSection load='6h2c' size='340' side='right'caption='[[6h2c]], [[Resolution|resolution]] 1.93Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6h2c]] is a 2 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=6H2C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6H2C FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.93Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=15P:POLYETHYLENE+GLYCOL+(N=34)'>15P</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CO2:CARBON+DIOXIDE'>CO2</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ISS:(2E)-3-[(4-HYDROXY-2-OXOBUTYL)AMINO]PROP-2-ENAL'>ISS</scene></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=6h2c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h2c OCA], [https://pdbe.org/6h2c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6h2c RCSB], [https://www.ebi.ac.uk/pdbsum/6h2c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6h2c ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Mycobacterium tuberculosis (Mtb), the main causative agent of tuberculosis (TB), is naturally resistant to beta-lactam antibiotics due to the production of the extended spectrum beta-lactamase BlaC. beta-Lactam/beta-lactamase inhibitor combination therapies can circumvent the BlaC-mediated resistance of Mtb and are promising treatment options against TB. However, still little is known of the exact mechanism of BlaC inhibition by the beta-lactamase inhibitors currently approved for clinical use, clavulanic acid, sulbactam, tazobactam, and avibactam. Here, we present the X-ray diffraction crystal structures of the acyl-enzyme adducts of wild-type BlaC with the four inhibitors. The +70 Da adduct derived from clavulanate and the trans-enamine acylation adducts of sulbactam and tazobactam are reported. BlaC in complex with avibactam revealed two inhibitor conformations. Preacylation binding could not be observed because inhibitor binding was not detected in BlaC variants carrying a substitution of the active site serine 70 to either alanine or cysteine, by crystallography, ITC or NMR. These results suggest that the catalytic serine 70 is necessary not only for enzyme acylation but also for increasing BlaC affinity for inhibitors in the preacylation state. The structure of BlaC with the serine to cysteine mutation showed a covalent linkage of the cysteine 70 Sgamma atom to the nearby amino group of lysine 73. The differences of adduct conformations between BlaC and other beta-lactamases are discussed. | |||
New Conformations of Acylation Adducts of Inhibitors of beta-Lactamase from Mycobacterium tuberculosis.,Tassoni R, Blok A, Pannu NS, Ubbink M Biochemistry. 2019 Feb 19;58(7):997-1009. doi: 10.1021/acs.biochem.8b01085. Epub , 2019 Jan 30. PMID:30632739<ref>PMID:30632739</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6h2c" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycobacterium tuberculosis]] | |||
[[Category: Pannu NS]] | |||
[[Category: Tassoni R]] | |||
[[Category: Ubbink M]] | |||
Latest revision as of 15:42, 6 November 2024
Structure of BlaC from Mycobacterium tuberculosis bound to the trans-enamine adduct derived from clavulanic acid.Structure of BlaC from Mycobacterium tuberculosis bound to the trans-enamine adduct derived from clavulanic acid.
Structural highlights
Publication Abstract from PubMedMycobacterium tuberculosis (Mtb), the main causative agent of tuberculosis (TB), is naturally resistant to beta-lactam antibiotics due to the production of the extended spectrum beta-lactamase BlaC. beta-Lactam/beta-lactamase inhibitor combination therapies can circumvent the BlaC-mediated resistance of Mtb and are promising treatment options against TB. However, still little is known of the exact mechanism of BlaC inhibition by the beta-lactamase inhibitors currently approved for clinical use, clavulanic acid, sulbactam, tazobactam, and avibactam. Here, we present the X-ray diffraction crystal structures of the acyl-enzyme adducts of wild-type BlaC with the four inhibitors. The +70 Da adduct derived from clavulanate and the trans-enamine acylation adducts of sulbactam and tazobactam are reported. BlaC in complex with avibactam revealed two inhibitor conformations. Preacylation binding could not be observed because inhibitor binding was not detected in BlaC variants carrying a substitution of the active site serine 70 to either alanine or cysteine, by crystallography, ITC or NMR. These results suggest that the catalytic serine 70 is necessary not only for enzyme acylation but also for increasing BlaC affinity for inhibitors in the preacylation state. The structure of BlaC with the serine to cysteine mutation showed a covalent linkage of the cysteine 70 Sgamma atom to the nearby amino group of lysine 73. The differences of adduct conformations between BlaC and other beta-lactamases are discussed. New Conformations of Acylation Adducts of Inhibitors of beta-Lactamase from Mycobacterium tuberculosis.,Tassoni R, Blok A, Pannu NS, Ubbink M Biochemistry. 2019 Feb 19;58(7):997-1009. doi: 10.1021/acs.biochem.8b01085. Epub , 2019 Jan 30. PMID:30632739[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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