View source for 8tqg


==Crystal Structure of Mtb Pks13 Thioesterase domain in complex with inhibitor X20419==
<StructureSection load='8tqg' size='340' side='right'caption='[[8tqg]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8tqg]] 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=8TQG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8TQG FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JR0:N-benzyl-2-{4-[4-(4,5-dimethoxy-1H-indole-2-carbonyl)piperazine-1-carbonyl]piperidin-1-yl}-6-methylpyrimidine-4-carboxamide'>JR0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=8tqg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8tqg OCA], [https://pdbe.org/8tqg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8tqg RCSB], [https://www.ebi.ac.uk/pdbsum/8tqg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8tqg ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PKS13_MYCTU PKS13_MYCTU] Involved in the biosynthesis of mycolic acids (PubMed:19436070, PubMed:23770708, PubMed:25467124). Forms, with FadD32, the initiation module of the mycolic condensation system (PubMed:19436070, PubMed:19477415, PubMed:25467124). Synthesizes, in coupled reaction with FadD32, the biosynthetic precursors of mycolic acids, alpha-alkyl beta-ketoacids, via the condensation of two long chain fatty acid derivatives, a very long meromycoloyl-AMP and a shorter 2-carboxyacyl-CoA (PubMed:19436070, PubMed:25467124). The acyl chain of the acyl-AMP produced by FadD32 is specifically transferred onto the N-terminal ACP domain of Pks13, and then transferred onto the KS domain. The extender unit carboxyacyl-CoA is specifically loaded onto the AT domain, which catalyzes the covalent attachment of the carboxyacyl chain to its active site, and its subsequent transfer onto the P-pant arm of the C-terminal ACP domain. The KS domain catalyzes the condensation between the two loaded fatty acyl chains to produce an alpha-alkyl beta-ketothioester linked to the C-ACP domain (PubMed:19436070). Then, the thioesterase-like domain acts as a transacylase and is responsible for both the release and the transfer of the alpha-alkyl beta-ketoacyl chain onto a polyol acceptor molecule, particularly trehalose, leading to the formation of the trehalose monomycolate precursor (PubMed:25467124).<ref>PMID:19436070</ref> <ref>PMID:19477415</ref> <ref>PMID:23770708</ref> <ref>PMID:25467124</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from Mycobacterium tuberculosis (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme. One of these inhibitors showed a favorable pharmacokinetic profile and demonstrated efficacy in an acute mouse model of tuberculosis (TB) infection. These findings and assay developments will aid in the advancement of TB drug discovery.

Inhibitors of the Thioesterase Activity of Mycobacterium tuberculosis Pks13 Discovered Using DNA-Encoded Chemical Library Screening.,Krieger IV, Yalamanchili S, Dickson P, Engelhart CA, Zimmerman MD, Wood J, Clary E, Nguyen J, Thornton N, Centrella PA, Chan B, Cuozzo JW, Gengenbacher M, Guie MA, Guilinger JP, Bienstock C, Hartl H, Hupp CD, Jetson R, Satoh T, Yeoman JTS, Zhang Y, Dartois V, Schnappinger D, Keefe AD, Sacchettini JC ACS Infect Dis. 2024 May 10;10(5):1561-1575. doi: 10.1021/acsinfecdis.3c00592. , Epub 2024 Apr 5. PMID:38577994<ref>PMID:38577994</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8tqg" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Krieger IV]]
[[Category: Sacchettini JC]]