7a1c
From Proteopedia
(Difference between revisions)
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==LdtMT2 with covalent adduct derived from N-Thio-beta-lactam 1a== | ==LdtMT2 with covalent adduct derived from N-Thio-beta-lactam 1a== | ||
| - | <StructureSection load='7a1c' size='340' side='right'caption='[[7a1c]]' scene=''> | + | <StructureSection load='7a1c' size='340' side='right'caption='[[7a1c]], [[Resolution|resolution]] 1.77Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7A1C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A1C FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7a1c]] 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=7A1C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A1C FirstGlance]. <br> |
| - | </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=7a1c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a1c OCA], [https://pdbe.org/7a1c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a1c RCSB], [https://www.ebi.ac.uk/pdbsum/7a1c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a1c ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr> |
| + | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SCH:S-METHYL-THIO-CYSTEINE'>SCH</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7a0z|7a0z]], [[7a10|7a10]], [[7a11|7a11]]</div></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> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7a1c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a1c OCA], [https://pdbe.org/7a1c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a1c RCSB], [https://www.ebi.ac.uk/pdbsum/7a1c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a1c 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;"> | ||
| + | == 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<ref>PMID:33826941</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7a1c" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Schnell R]] | + | [[Category: Myctu]] |
| - | [[Category: Steiner | + | [[Category: Schnell, R]] |
| + | [[Category: Steiner, E M]] | ||
| + | [[Category: Antibiotic]] | ||
| + | [[Category: Beta-lactam]] | ||
| + | [[Category: Cell wall]] | ||
| + | [[Category: Covalent inhibitor]] | ||
| + | [[Category: Ligase]] | ||
| + | [[Category: Mycobacterium tuberculosis]] | ||
| + | [[Category: Peptidoglycan]] | ||
| + | [[Category: Transpeptidase]] | ||
Revision as of 08:57, 29 September 2021
LdtMT2 with covalent adduct derived from N-Thio-beta-lactam 1a
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