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| | ==Crystal structure of Mycobacterium tuberculosis L,D-transpeptidase 2 with Doripenem adduct== | | ==Crystal structure of Mycobacterium tuberculosis L,D-transpeptidase 2 with Doripenem adduct== |
| - | <StructureSection load='5dvp' size='340' side='right' caption='[[5dvp]], [[Resolution|resolution]] 2.18Å' scene=''> | + | <StructureSection load='5dvp' size='340' side='right'caption='[[5dvp]], [[Resolution|resolution]] 2.18Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5dvp]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DVP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DVP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5dvp]] 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=5DVP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DVP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DRW:(2S,3R,4S)-2-[(2S,3R)-3-HYDROXY-1-OXOBUTAN-2-YL]-3-METHYL-4-({(3S,5S)-5-[(SULFAMOYLAMINO)METHYL]PYRROLIDIN-3-YL}SULFANYL)-3,4-DIHYDRO-2H-PYRROLE-5-CARBOXYLIC+ACID'>DRW</scene>, <scene name='pdbligand=POA:PHOSPHONOACETALDEHYDE'>POA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.18Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5duj|5duj]], [[5du7|5du7]], [[5dvq|5dvq]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DRW:(2S,3R,4S)-2-[(2S,3R)-3-HYDROXY-1-OXOBUTAN-2-YL]-3-METHYL-4-({(3S,5S)-5-[(SULFAMOYLAMINO)METHYL]PYRROLIDIN-3-YL}SULFANYL)-3,4-DIHYDRO-2H-PYRROLE-5-CARBOXYLIC+ACID'>DRW</scene>, <scene name='pdbligand=POA:PHOSPHONOACETALDEHYDE'>POA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ldtB, lppS, Rv2518c, RVBD_2518c, P425_02624 ([http://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=5dvp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dvp OCA], [https://pdbe.org/5dvp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dvp RCSB], [https://www.ebi.ac.uk/pdbsum/5dvp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dvp ProSAT]</span></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=5dvp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dvp OCA], [http://pdbe.org/5dvp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dvp RCSB], [http://www.ebi.ac.uk/pdbsum/5dvp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5dvp 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: Myctu]] | + | [[Category: Large Structures]] |
| - | [[Category: Kumar, P]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Lamichhane, G]] | + | [[Category: Kumar P]] |
| - | [[Category: Cell wall enzyme]] | + | [[Category: Lamichhane G]] |
| - | [[Category: Peptidoglycan synthesis enzyme]]
| + | |
| - | [[Category: Transferase]]
| + | |
| 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
Bacterial survival requires an intact peptidoglycan layer, a three-dimensional exoskeleton that encapsulates the cytoplasmic membrane. Historically, the final steps of peptidoglycan synthesis are known to be carried out by D,D-transpeptidases, enzymes that are inhibited by the beta-lactams, which constitute >50% of all antibacterials in clinical use. Here, we show that the carbapenem subclass of beta-lactams are distinctly effective not only because they inhibit D,D-transpeptidases and are poor substrates for beta-lactamases, but primarily because they also inhibit non-classical transpeptidases, namely the L,D-transpeptidases, which generate the majority of linkages in the peptidoglycan of mycobacteria. We have characterized the molecular mechanisms responsible for inhibition of L,D-transpeptidases of Mycobacterium tuberculosis and a range of bacteria including ESKAPE pathogens, and used this information to design, synthesize and test simplified carbapenems with potent antibacterial activity.
Non-classical transpeptidases yield insight into new antibacterials.,Kumar P, Kaushik A, Lloyd EP, Li SG, Mattoo R, Ammerman NC, Bell DT, Perryman AL, Zandi TA, Ekins S, Ginell SL, Townsend CA, Freundlich JS, Lamichhane G Nat Chem Biol. 2016 Nov 7. doi: 10.1038/nchembio.2237. PMID:27820797[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
- ↑ Kumar P, Kaushik A, Lloyd EP, Li SG, Mattoo R, Ammerman NC, Bell DT, Perryman AL, Zandi TA, Ekins S, Ginell SL, Townsend CA, Freundlich JS, Lamichhane G. Non-classical transpeptidases yield insight into new antibacterials. Nat Chem Biol. 2016 Nov 7. doi: 10.1038/nchembio.2237. PMID:27820797 doi:http://dx.doi.org/10.1038/nchembio.2237
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