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| | ==Crystal structure of the Mycobacterium tuberculosis L,D-transpeptidase-2 (LdtMt2) BC-module with thionitrobenzoate (TNB) adduct at the active site cysteine-354== | | ==Crystal structure of the Mycobacterium tuberculosis L,D-transpeptidase-2 (LdtMt2) BC-module with thionitrobenzoate (TNB) adduct at the active site cysteine-354== |
| - | <StructureSection load='5lb1' size='340' side='right' caption='[[5lb1]], [[Resolution|resolution]] 1.55Å' scene=''> | + | <StructureSection load='5lb1' size='340' side='right'caption='[[5lb1]], [[Resolution|resolution]] 1.55Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5lb1]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LB1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LB1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5lb1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LB1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LB1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MNB:5-MERCAPTO-2-NITRO-BENZOIC+ACID'>MNB</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]] 1.55Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4huc|4huc]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MNB:5-MERCAPTO-2-NITRO-BENZOIC+ACID'>MNB</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5lb1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lb1 OCA], [http://pdbe.org/5lb1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lb1 RCSB], [http://www.ebi.ac.uk/pdbsum/5lb1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lb1 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=5lb1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lb1 OCA], [https://pdbe.org/5lb1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5lb1 RCSB], [https://www.ebi.ac.uk/pdbsum/5lb1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5lb1 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Schneider, G]] | + | [[Category: Large Structures]] |
| - | [[Category: Schnell, R]]
| + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Steiner, E M]]
| + | [[Category: Schneider G]] |
| - | [[Category: Cell wall]]
| + | [[Category: Schnell R]] |
| - | [[Category: Mycobacterium tuberculosis]] | + | [[Category: Steiner EM]] |
| - | [[Category: Peptidoglycan]] | + | |
| - | [[Category: Transferase]] | + | |
| - | [[Category: Transpeptidase]] | + | |
| Structural highlights
Function
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.[1]
Publication Abstract from PubMed
beta-lactam antibiotics represent a novel direction in the chemotherapy of tuberculosis that brings the peptidoglycan layer of the complex mycobacterial cell wall in focus as therapeutic target. Peptidoglycan stability in Mycobacterium tuberculosis especially during infection relies on the non-conventional peptide cross-links formed by L,D-transpeptidases. These enzymes are known to be inhibited by beta-lactams, primarily carbapenems, leading to a stable covalent modification at the enzyme active site. A panel of sixteen beta-lactams antibiotics was characterized by inhibition kinetics, mass spectrometry and x-ray crystallography to identify efficient compounds and study their action on the essential transpeptidase LdtMt2 . Members of the carbapenem class displayed fast binding kinetics, but faropenem, a penem type compound showed a 3-4 times higher rate in the adduct formation. In three cases mass spectrometry indicated that carbapenems may undergo decarboxylation, while faropenem decomposition following the acylation step results in a small 87 Da beta-OH-butyryl adduct bound at the catalytic cysteine residue. The crystal structure of LdtMt2 at 1.54 A resolution with this fragment bound revealed that the protein adopts a closed conformation that shields the thioester bond from the solvent, which is in line with the high stability of this dead-end complex observed also in biochemical assays. This article is protected by copyright. All rights reserved.
Binding and processing of beta-lactam antibiotics by the transpeptidase LdtMt2 from Mycobacterium tuberculosis.,Steiner EM, Schneider G, Schnell R FEBS J. 2017 Jan 11. doi: 10.1111/febs.14010. PMID:28075068[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cordillot M, Dubee V, Triboulet S, Dubost L, Marie A, Hugonnet JE, Arthur M, Mainardi JL. In vitro cross-linking of Mycobacterium tuberculosis peptidoglycan by L,D-transpeptidases and inactivation of these enzymes by carbapenems. Antimicrob Agents Chemother. 2013 Dec;57(12):5940-5. doi: 10.1128/AAC.01663-13., Epub 2013 Sep 16. PMID:24041897 doi:http://dx.doi.org/10.1128/AAC.01663-13
- ↑ Steiner EM, Schneider G, Schnell R. Binding and processing of beta-lactam antibiotics by the transpeptidase LdtMt2 from Mycobacterium tuberculosis. FEBS J. 2017 Jan 11. doi: 10.1111/febs.14010. PMID:28075068 doi:http://dx.doi.org/10.1111/febs.14010
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