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| | <StructureSection load='7a1e' size='340' side='right'caption='[[7a1e]], [[Resolution|resolution]] 1.77Å' scene=''> | | <StructureSection load='7a1e' size='340' side='right'caption='[[7a1e]], [[Resolution|resolution]] 1.77Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7a1e]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7A1E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A1E FirstGlance]. <br> | + | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7A1E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A1E FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=SDQ:phenylmethanethiol'>SDQ</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.77Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7a10|7a10]], [[7a11|7a11]], [[7a0z|7a0z]], [[7a1c|7a1c]]</div></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=SDQ:phenylmethanethiol'>SDQ</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ldtB, lppS, Rv2518c, RVBD_2518c, P425_02624 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr>
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| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7a1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a1e OCA], [https://pdbe.org/7a1e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a1e RCSB], [https://www.ebi.ac.uk/pdbsum/7a1e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a1e ProSAT]</span></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=7a1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a1e OCA], [https://pdbe.org/7a1e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a1e RCSB], [https://www.ebi.ac.uk/pdbsum/7a1e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a1e ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Function == | |
| - | [[https://www.uniprot.org/uniprot/LDT2_MYCTU LDT2_MYCTU]] Generates 3->3 cross-links in peptidoglycan, catalyzing the cleavage of the mDap(3)-D-Ala(4) bond of a tetrapeptide donor stem and the formation of a bond between the carbonyl of mDap(3) of the donor stem and the side chain of mDap(3) of the acceptor stem. Is specific for donor substrates containing a stem tetrapeptide since it cannot use pentapeptide stems.<ref>PMID:24041897</ref> | |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Myctu]]
| + | [[Category: Schnell R]] |
| - | [[Category: Schnell, R]] | + | [[Category: Steiner EM]] |
| - | [[Category: Steiner, E M]] | + | |
| - | [[Category: Antibiotic]]
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| - | [[Category: Beta-lactam]]
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| - | [[Category: Cell wall]]
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| - | [[Category: Covalent inhibitor]]
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| - | [[Category: Ligase]]
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| - | [[Category: Mycobacterium tuberculosis]]
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| - | [[Category: Peptidoglycan]]
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| - | [[Category: Transpeptidase]]
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| Structural highlights
Publication Abstract from PubMed
Effective treatment of tuberculosis is frequently hindered by the emerging antimicrobial resistance of Mycobacterium tuberculosis. The present study evaluates monocyclic beta-lactam compounds targeting the mycobacterial cell wall remodeling. Novel N-thio-beta-lactams were designed, synthesized, and characterized on the L,D-transpeptidase-2, a validated target in M. tuberculosis. The candidates were evaluated in biochemical assays identifying five compounds presenting target-specific kinetic constants equal or superior to meropenem, a carbapenem currently considered for tuberculosis therapy. Mass spectrometry in line with the crystal structures of five target-ligand complexes revealed that the N-thio-beta-lactams act via an unconventional mode of adduct formation, transferring the thio-residues from the lactam ring to the active-site cysteine of LdtMt2. The resulting stable adducts lead to a long-term inactivation of the target protein. Finally, the candidates were evaluated in vitro against a drug-susceptible and multidrug-resistant clinical isolates of M. tuberculosis, confirming the antimycobacterial effect of these novel compounds.
N-Thio-beta-lactams targeting L,D-transpeptidase-2, with activity against drug-resistant strains of Mycobacterium tuberculosis.,Martelli G, Pessatti TB, Steiner EM, Cirillo M, Caso C, Bisognin F, Landreh M, Monte PD, Giacomini D, Schnell R Cell Chem Biol. 2021 Mar 30. pii: S2451-9456(21)00147-1. doi:, 10.1016/j.chembiol.2021.03.008. PMID:33826941[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Martelli G, Pessatti TB, Steiner EM, Cirillo M, Caso C, Bisognin F, Landreh M, Monte PD, Giacomini D, Schnell R. N-Thio-beta-lactams targeting L,D-transpeptidase-2, with activity against drug-resistant strains of Mycobacterium tuberculosis. Cell Chem Biol. 2021 Mar 30. pii: S2451-9456(21)00147-1. doi:, 10.1016/j.chembiol.2021.03.008. PMID:33826941 doi:http://dx.doi.org/10.1016/j.chembiol.2021.03.008
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