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| | <StructureSection load='5dc2' size='340' side='right'caption='[[5dc2]], [[Resolution|resolution]] 2.18Å' scene=''> | | <StructureSection load='5dc2' size='340' side='right'caption='[[5dc2]], [[Resolution|resolution]] 2.18Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5dc2]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycto Mycto]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DC2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DC2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5dc2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_CDC1551 Mycobacterium tuberculosis CDC1551]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DC2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DC2 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=58U:(4S)-4-METHYL-2,5,7-TRIOXOHEPTANOIC+ACID'>58U</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=58U:(4S)-4-METHYL-2,5,7-TRIOXOHEPTANOIC+ACID'>58U</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3tur|3tur]], [[5dcc|5dcc]]</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=5dc2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dc2 OCA], [https://pdbe.org/5dc2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dc2 RCSB], [https://www.ebi.ac.uk/pdbsum/5dc2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dc2 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ldtB, MT2594, V735_02606 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83331 MYCTO])</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=5dc2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dc2 OCA], [http://pdbe.org/5dc2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dc2 RCSB], [http://www.ebi.ac.uk/pdbsum/5dc2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5dc2 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/LDT2_MYCTO LDT2_MYCTO]] 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. Is essential for virulence in a mouse model of acute infection.<ref>PMID:20305661</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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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Mycto]] | + | [[Category: Mycobacterium tuberculosis CDC1551]] |
| - | [[Category: Basta, L]] | + | [[Category: Basta L]] |
| - | [[Category: Bianchet, M A]] | + | [[Category: Bianchet MA]] |
| - | [[Category: Lamichhane, G]] | + | [[Category: Lamichhane G]] |
| - | [[Category: Pan, Y]] | + | [[Category: Pan Y]] |
| - | [[Category: Carbapenems biapenem-adduct]]
| + | |
| - | [[Category: D-transpeptidase]]
| + | |
| - | [[Category: Ldtmt2]]
| + | |
| - | [[Category: Mycobacterium tuberculosis]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
5dc2 is a 2 chain structure with sequence from Mycobacterium tuberculosis CDC1551. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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
BACKGROUND: The carbapenem subclass of beta-lactams is among the most potent antibiotics available today. Emerging evidence shows that, unlike other subclasses of beta-lactams, carbapenems bind to and inhibit non-classical transpeptidases (L,D-transpeptidases) that generate 3 --> 3 linkages in bacterial peptidoglycan. The carbapenems biapenem and tebipenem exhibit therapeutically valuable potencies against Mycobacterium tuberculosis (Mtb). RESULTS: Here, we report the X-ray crystal structures of Mtb L,D-transpeptidase-2 (LdtMt2) complexed with biapenem or tebipenem. Despite significant variations in carbapenem sulfur side chains, biapenem and tebipenem ultimately form an identical adduct that docks to the outer cavity of LdtMt2. We propose that this common adduct is an enzyme catalyzed decomposition of the carbapenem adduct by a mechanism similar to S-conjugate elimination by beta-lyases. CONCLUSION: The results presented here demonstrate biapenem and tebipenem bind to the outer cavity of LdtMt2, covalently inactivate the enzyme, and subsequently degrade via an S-conjugate elimination mechanism. We discuss structure based drug design based on the findings and propose that the S-conjugate elimination can be leveraged to design novel agents to deliver and locally release antimicrobial factors to act synergistically with the carbapenem carrier.
Structural insight into the inactivation of Mycobacterium tuberculosis non-classical transpeptidase LdtMt2 by biapenem and tebipenem.,Bianchet MA, Pan YH, Basta LAB, Saavedra H, Lloyd EP, Kumar P, Mattoo R, Townsend CA, Lamichhane G BMC Biochem. 2017 May 25;18(1):8. doi: 10.1186/s12858-017-0082-4. PMID:28545389[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
- ↑ Bianchet MA, Pan YH, Basta LAB, Saavedra H, Lloyd EP, Kumar P, Mattoo R, Townsend CA, Lamichhane G. Structural insight into the inactivation of Mycobacterium tuberculosis non-classical transpeptidase LdtMt2 by biapenem and tebipenem. BMC Biochem. 2017 May 25;18(1):8. doi: 10.1186/s12858-017-0082-4. PMID:28545389 doi:http://dx.doi.org/10.1186/s12858-017-0082-4
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