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| | ==Crystal structure of L,D-transpeptidase 3 from Mycobacterium tuberculosis at 1.32 A resolution== | | ==Crystal structure of L,D-transpeptidase 3 from Mycobacterium tuberculosis at 1.32 A resolution== |
| - | <StructureSection load='6d4k' size='340' side='right' caption='[[6d4k]], [[Resolution|resolution]] 1.32Å' scene=''> | + | <StructureSection load='6d4k' size='340' side='right'caption='[[6d4k]], [[Resolution|resolution]] 1.32Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6d4k]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6D4K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6D4K FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6d4k]] is a 1 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=6D4K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6D4K FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</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]] 1.32Å</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=6d4k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d4k OCA], [http://pdbe.org/6d4k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6d4k RCSB], [http://www.ebi.ac.uk/pdbsum/6d4k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6d4k ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</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=6d4k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d4k OCA], [https://pdbe.org/6d4k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6d4k RCSB], [https://www.ebi.ac.uk/pdbsum/6d4k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6d4k ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/LDT3_MYCTU LDT3_MYCTU]] Probable L,D-transpeptidase that may perform as-yet-unknown cross-linking reactions in M.tuberculosis. Is not able to generate 3->3 cross-links in peptidoglycan, using tetrapeptide stems as acyl donor substrates. May function in the anchoring of proteins to peptidoglycan.<ref>PMID:24041897</ref> | + | [https://www.uniprot.org/uniprot/LDT3_MYCTU LDT3_MYCTU] Probable L,D-transpeptidase that may perform as-yet-unknown cross-linking reactions in M.tuberculosis. Is not able to generate 3->3 cross-links in peptidoglycan, using tetrapeptide stems as acyl donor substrates. May function in the anchoring of proteins to peptidoglycan.<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: Dias, M V.B]] | + | [[Category: Large Structures]] |
| - | [[Category: Libreros, G A]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Apo-form]] | + | [[Category: Dias MVB]] |
| - | [[Category: Transferase]] | + | [[Category: Libreros GA]] |
| Structural highlights
Function
LDT3_MYCTU Probable L,D-transpeptidase that may perform as-yet-unknown cross-linking reactions in M.tuberculosis. Is not able to generate 3->3 cross-links in peptidoglycan, using tetrapeptide stems as acyl donor substrates. May function in the anchoring of proteins to peptidoglycan.[1]
Publication Abstract from PubMed
Targeting Mycobacterium tuberculosis peptidoglycans with beta-lactam antibiotics represents a strategy to address increasing resistance to antitubercular drugs. beta-Lactams inhibit peptidoglycan synthases such as l,d-transpeptidases, a group of carbapenem-sensitive enzymes that stabilize peptidoglycans through 3 --> 3 cross-links. M. tuberculosis encodes five l,d-transpeptidases (LdtMt1-5), of which LdtMt3 is one of the less understood. Herein, we structurally characterized the apo and faropenem-acylated forms of LdtMt3 at 1.3 and 1.8 A resolution, respectively. These structures revealed a fold and catalytic diad similar to those of other LdtsMt enzymes, supporting its involvement in transpeptidation reactions despite divergences in active site size and charges. The LdtMt3-faropenem structure indicated that faropenem is degraded after Cys-246 acylation, and possibly only a beta-OH-butyrate or an acetyl group (C2H3O) covalently attached to the enzyme remains, an observation that strongly supports the notion that LdtMt3 is inactivated by beta-lactams. Docking simulations with intact beta-lactams predicted key LdtMt3 residues that interact with these antibiotics. We also characterized the heat of acylation involved in the binding and reaction of LdtMt3 for ten beta-lactams belonging to four different classes, and imipenem had the highest inactivation constant. This work provides key insights into the structure, binding mechanisms, and degradation of beta-lactams by LdtMt3, which may be useful for the development of additional beta-lactams with potential antitubercular activity.
Structural Basis for the Interaction and Processing of beta-Lactam Antibiotics by l,d-Transpeptidase 3 (LdtMt3) from Mycobacterium tuberculosis.,Libreros-Zuniga GA, Dos Santos Silva C, Salgado Ferreira R, Dias MVB ACS Infect Dis. 2019 Feb 8;5(2):260-271. doi: 10.1021/acsinfecdis.8b00244. Epub, 2018 Dec 28. PMID:30556998[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
- ↑ Libreros-Zuniga GA, Dos Santos Silva C, Salgado Ferreira R, Dias MVB. Structural Basis for the Interaction and Processing of beta-Lactam Antibiotics by l,d-Transpeptidase 3 (LdtMt3) from Mycobacterium tuberculosis. ACS Infect Dis. 2019 Feb 8;5(2):260-271. doi: 10.1021/acsinfecdis.8b00244. Epub, 2018 Dec 28. PMID:30556998 doi:http://dx.doi.org/10.1021/acsinfecdis.8b00244
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