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4gsq

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==Structural basis for the inhibition of Mycobacterium tuberculosis L,D-transpeptidase by meropenem, a drug effective against extensively drug-resistant strains==
==Structural basis for the inhibition of Mycobacterium tuberculosis L,D-transpeptidase by meropenem, a drug effective against extensively drug-resistant strains==
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<StructureSection load='4gsq' size='340' side='right' caption='[[4gsq]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
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<StructureSection load='4gsq' size='340' side='right'caption='[[4gsq]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4gsq]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GSQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GSQ FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4gsq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GSQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GSQ FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gsr|4gsr]], [[4gsu|4gsu]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">lppS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 Mycobacterium tuberculosis])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4gsq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gsq OCA], [https://pdbe.org/4gsq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gsq RCSB], [https://www.ebi.ac.uk/pdbsum/4gsq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gsq ProSAT]</span></td></tr>
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<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=4gsq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gsq OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gsq RCSB], [http://www.ebi.ac.uk/pdbsum/4gsq PDBsum]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://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>
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Difficulty in the treatment of tuberculosis and growing drug resistance in Mycobacterium tuberculosis (Mtb) are a global health issue. Carbapenems inactivate L,D-transpeptidases; meropenem, when administered with clavulanate, showed in vivo activity against extensively drug-resistant Mtb strains. LdtMt2 (Rv2518c), one of two functional L,D-transpeptidases in Mtb, is predominantly expressed over LdtMt1 (Rv0116c). Here, the crystal structure of N-terminally truncated LdtMt2 (residues Leu131-Ala408) is reported in both ligand-free and meropenem-bound forms. The structure of meropenem-inhibited LdtMt2 provides a detailed structural view of the interactions between a carbapenem drug and Mtb L,D-transpeptidase. The structures revealed that the catalytic L,D-transpeptidase domain of LdtMt2 is preceded by a bacterial immunogloblin-like Big_5 domain and is followed by an extended C-terminal tail that interacts with both domains. Furthermore, it is shown using mass analyses that meropenem acts as a suicide inhibitor of LdtMt2. Upon acylation of the catalytic Cys354 by meropenem, the `active-site lid' undergoes a large conformational change to partially cover the active site so that the bound meropenem is accessible to the bulk solvent via three narrow paths. This work will facilitate structure-guided discovery of L,D-transpeptidase inhibitors as novel antituberculosis drugs against drug-resistant Mtb.
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Structural basis for the inhibition of Mycobacterium tuberculosis L,D-transpeptidase by meropenem, a drug effective against extensively drug-resistant strains.,Kim HS, Kim J, Im HN, Yoon JY, An DR, Yoon HJ, Kim JY, Min HK, Kim SJ, Lee JY, Han BW, Suh SW Acta Crystallogr D Biol Crystallogr. 2013 Mar;69(Pt 3):420-31. doi:, 10.1107/S0907444912048998. Epub 2013 Feb 16. PMID:23519417<ref>PMID:23519417</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Large Structures]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Mycobacterium tuberculosis]]
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[[Category: An, D R]]
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[[Category: An DR]]
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[[Category: Han, B W]]
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[[Category: Han BW]]
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[[Category: Im, H N]]
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[[Category: Im HN]]
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[[Category: Kim, H S]]
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[[Category: Kim HS]]
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[[Category: Kim, J]]
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[[Category: Kim J]]
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[[Category: Kim, J Y]]
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[[Category: Kim JY]]
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[[Category: Kim, S J]]
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[[Category: Kim S-J]]
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[[Category: Lee, J Y]]
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[[Category: Lee JY]]
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[[Category: Min, H K]]
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[[Category: Min HK]]
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[[Category: Suh, S W]]
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[[Category: Suh SW]]
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[[Category: Yoon, H J]]
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[[Category: Yoon HJ]]
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[[Category: Yoon, J Y]]
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[[Category: Yoon JY]]
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[[Category: D-transpeptidase]]
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[[Category: Transferase]]
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Current revision

Structural basis for the inhibition of Mycobacterium tuberculosis L,D-transpeptidase by meropenem, a drug effective against extensively drug-resistant strains

PDB ID 4gsq

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