8oe1: Difference between revisions
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==Structure of P167S BlaC from Mycobacterium tuberculosis at pH 5== | |||
<StructureSection load='8oe1' size='340' side='right'caption='[[8oe1]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8oe1]] 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=8OE1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8OE1 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]] 1.9Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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=8oe1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8oe1 OCA], [https://pdbe.org/8oe1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8oe1 RCSB], [https://www.ebi.ac.uk/pdbsum/8oe1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8oe1 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/A0A655AHQ9_MYCTX A0A655AHQ9_MYCTX] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The beta-lactamase BlaC conveys resistance to a broad spectrum of beta-lactam antibiotics to its host Mycobacterium tuberculosis but poorly hydrolyzes third-generation cephalosporins, such as ceftazidime. Variants of other beta-lactamases have been reported to gain activity against ceftazidime at the cost of the native activity. To understand this trade-off, laboratory evolution was performed, screening for enhanced ceftazidime activity. The variant BlaC Pro167Ser shows faster breakdown of ceftazidime, poor hydrolysis of ampicillin and only moderately reduced activity against nitrocefin. NMR spectroscopy, crystallography and kinetic assays demonstrate that the resting state of BlaC P167S exists in an open and a closed state. The open state is more active in the hydrolysis of ceftazidime. In this state the catalytic residue Glu166, generally believed to be involved in the activation of the water molecule required for deacylation, is rotated away from the active site, suggesting it plays no role in the hydrolysis of ceftazidime. In the closed state, deacylation of the BlaC-ceftazidime adduct is slow, while hydrolysis of nitrocefin, which requires the presence of Glu166 in the active site, is barely affected, providing a structural explanation for the trade-off in activities. | |||
Enhanced activity against a third-generation cephalosporin by destabilization of the active site of a class A beta-lactamase.,Sun J, Chikunova A, Boyle AL, Voskamp P, Timmer M, Ubbink M Int J Biol Macromol. 2023 Aug 6;250:126160. doi: 10.1016/j.ijbiomac.2023.126160. PMID:37549761<ref>PMID:37549761</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Chikunova | <div class="pdbe-citations 8oe1" style="background-color:#fffaf0;"></div> | ||
[[Category: Sun | == References == | ||
[[Category: Ubbink | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycobacterium tuberculosis]] | |||
[[Category: Chikunova A]] | |||
[[Category: Sun J]] | |||
[[Category: Ubbink M]] | |||
Revision as of 08:55, 23 August 2023
Structure of P167S BlaC from Mycobacterium tuberculosis at pH 5Structure of P167S BlaC from Mycobacterium tuberculosis at pH 5
Structural highlights
FunctionPublication Abstract from PubMedThe beta-lactamase BlaC conveys resistance to a broad spectrum of beta-lactam antibiotics to its host Mycobacterium tuberculosis but poorly hydrolyzes third-generation cephalosporins, such as ceftazidime. Variants of other beta-lactamases have been reported to gain activity against ceftazidime at the cost of the native activity. To understand this trade-off, laboratory evolution was performed, screening for enhanced ceftazidime activity. The variant BlaC Pro167Ser shows faster breakdown of ceftazidime, poor hydrolysis of ampicillin and only moderately reduced activity against nitrocefin. NMR spectroscopy, crystallography and kinetic assays demonstrate that the resting state of BlaC P167S exists in an open and a closed state. The open state is more active in the hydrolysis of ceftazidime. In this state the catalytic residue Glu166, generally believed to be involved in the activation of the water molecule required for deacylation, is rotated away from the active site, suggesting it plays no role in the hydrolysis of ceftazidime. In the closed state, deacylation of the BlaC-ceftazidime adduct is slow, while hydrolysis of nitrocefin, which requires the presence of Glu166 in the active site, is barely affected, providing a structural explanation for the trade-off in activities. Enhanced activity against a third-generation cephalosporin by destabilization of the active site of a class A beta-lactamase.,Sun J, Chikunova A, Boyle AL, Voskamp P, Timmer M, Ubbink M Int J Biol Macromol. 2023 Aug 6;250:126160. doi: 10.1016/j.ijbiomac.2023.126160. PMID:37549761[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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