4gsu: Difference between revisions
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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== | |||
<StructureSection load='4gsu' size='340' side='right' caption='[[4gsu]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
{ | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4gsu]] is a 2 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=4GSU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GSU FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DWZ:(2S,3R,4S)-4-{[(3S,5S)-5-(DIMETHYLCARBAMOYL)PYRROLIDIN-3-YL]SULFANYL}-2-[(1S,2R)-1-FORMYL-2-HYDROXYPROPYL]-3-METHYL-3,4-DIHYDRO-2H-PYRROLE-5-CARBOXYLIC+ACID'>DWZ</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gsq|4gsq]], [[4gsr|4gsr]]</td></tr> | |||
<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> | |||
<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=4gsu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gsu OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gsu RCSB], [http://www.ebi.ac.uk/pdbsum/4gsu PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Mycobacterium tuberculosis]] | [[Category: Mycobacterium tuberculosis]] | ||
[[Category: An, D R | [[Category: An, D R]] | ||
[[Category: Han, B W | [[Category: Han, B W]] | ||
[[Category: Im, H N | [[Category: Im, H N]] | ||
[[Category: Kim, H S | [[Category: Kim, H S]] | ||
[[Category: Kim, J | [[Category: Kim, J]] | ||
[[Category: Kim, J Y | [[Category: Kim, J Y]] | ||
[[Category: Kim, S J | [[Category: Kim, S J]] | ||
[[Category: Lee, J Y | [[Category: Lee, J Y]] | ||
[[Category: Min, H K | [[Category: Min, H K]] | ||
[[Category: Suh, S W | [[Category: Suh, S W]] | ||
[[Category: Yoon, H J | [[Category: Yoon, H J]] | ||
[[Category: Yoon, J Y | [[Category: Yoon, J Y]] | ||
[[Category: D-transpeptidase]] | [[Category: D-transpeptidase]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
