4df6: Difference between revisions
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The | ==Crystal Structure of the inhibitor NXL104 Covalent Adduct with TB B-lactamase== | ||
<StructureSection load='4df6' size='340' side='right'caption='[[4df6]], [[Resolution|resolution]] 2.29Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4df6]] 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=4DF6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DF6 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]] 2.29Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NXL:(2S,5R)-1-FORMYL-5-[(SULFOOXY)AMINO]PIPERIDINE-2-CARBOXAMIDE'>NXL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=4df6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4df6 OCA], [https://pdbe.org/4df6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4df6 RCSB], [https://www.ebi.ac.uk/pdbsum/4df6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4df6 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/BLAC_MYCTU BLAC_MYCTU] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
NXL104 is a novel beta-lactamase inhibitor with a non-lactam structural scaffold. Our kinetic and mass spectrometric analysis demonstrates that NXL104 quantitatively inhibits BlaC, the only chromosomally encoded beta-lactamase from Mycobacterium tuberculosis, by forming a carbamyl adduct with the enzyme. The inhibition efficiency (k(2)/K) of NXL104 was shown to be more than 100-fold lower than that of clavulanate, a classical beta-lactamase inhibitor, which is probably caused by the bulky rings of NXL104. However, the decarbamylation rate constant (k(3)) was determined to be close to zero. The BlaC-NXL104 adduct remained stable for at least 48 h, while the hydrolysis of the BlaC-clavulanate adduct was observed after 2 days. The three-dimensional crystal structure of the BlaC--NXL104 carbamyl adduct was determined at a resolution of 2.3 A. Interestingly, the sulfate group of NXL104 occupies the position of a phosphate ion in the structure of the BlaC-clavulanate adduct and is hydrogen bonded to residues Ser128, Thr237, and Thr239. Favorable interactions are also seen in the electrostatic potential map. We propose that these additional interactions, as well as the intrinsic stability of the carbamyl linkage, contribute to the extraordinary stability of the BlaC-NXL104 adduct. | |||
NXL104 Irreversibly Inhibits the beta-Lactamase from Mycobacterium tuberculosis.,Xu H, Hazra S, Blanchard JS Biochemistry. 2012 May 22. PMID:22587688<ref>PMID:22587688</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4df6" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycobacterium tuberculosis]] | |||
[[Category: Blanchard J]] | |||
[[Category: Hazra S]] | |||
Latest revision as of 11:18, 9 October 2024
Crystal Structure of the inhibitor NXL104 Covalent Adduct with TB B-lactamaseCrystal Structure of the inhibitor NXL104 Covalent Adduct with TB B-lactamase
Structural highlights
FunctionPublication Abstract from PubMedNXL104 is a novel beta-lactamase inhibitor with a non-lactam structural scaffold. Our kinetic and mass spectrometric analysis demonstrates that NXL104 quantitatively inhibits BlaC, the only chromosomally encoded beta-lactamase from Mycobacterium tuberculosis, by forming a carbamyl adduct with the enzyme. The inhibition efficiency (k(2)/K) of NXL104 was shown to be more than 100-fold lower than that of clavulanate, a classical beta-lactamase inhibitor, which is probably caused by the bulky rings of NXL104. However, the decarbamylation rate constant (k(3)) was determined to be close to zero. The BlaC-NXL104 adduct remained stable for at least 48 h, while the hydrolysis of the BlaC-clavulanate adduct was observed after 2 days. The three-dimensional crystal structure of the BlaC--NXL104 carbamyl adduct was determined at a resolution of 2.3 A. Interestingly, the sulfate group of NXL104 occupies the position of a phosphate ion in the structure of the BlaC-clavulanate adduct and is hydrogen bonded to residues Ser128, Thr237, and Thr239. Favorable interactions are also seen in the electrostatic potential map. We propose that these additional interactions, as well as the intrinsic stability of the carbamyl linkage, contribute to the extraordinary stability of the BlaC-NXL104 adduct. NXL104 Irreversibly Inhibits the beta-Lactamase from Mycobacterium tuberculosis.,Xu H, Hazra S, Blanchard JS Biochemistry. 2012 May 22. PMID:22587688[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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