View source for 8s53


==X-ray crystal structure of CYP142 from Mycobacterium tuberculosis in complex with a fragment bound in two poses==
<StructureSection load='8s53' size='340' side='right'caption='[[8s53]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8s53]] is a 1 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=8S53 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8S53 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]] 1.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3QO:4-BENZYLPYRIDINE'>3QO</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</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=8s53 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8s53 OCA], [https://pdbe.org/8s53 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8s53 RCSB], [https://www.ebi.ac.uk/pdbsum/8s53 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8s53 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CP142_MYCTU CP142_MYCTU] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Mycobacterium tuberculosis (Mtb) is the world's most deadly infectious pathogen and new drugs are urgently required to combat the emergence of multi- (MDR) and extensively- (XDR) drug resistant strains. The bacterium specifically upregulates sterol uptake pathways in infected macrophages and the metabolism of host-derived cholesterol is essential for Mtb's long-term survival in vivo. Here, we report the development of antitubercular small molecules that inhibit the Mtb cholesterol oxidases CYP125 and CYP142, which catalyze the initial step of cholesterol metabolism. An efficient biophysical fragment screen was used to characterize the structure-activity relationships of CYP125 and CYP142, and identify a non-azole small molecule 1a that can bind to the heme cofactor of both enzymes. A structure-guided fragment-linking strategy was used to optimize the binding affinity of 1a, yielding a potent dual CYP125/142 inhibitor 5m (K(D) CYP125/CYP142 = 0.04/0.16 muM). Compound 5m potently inhibits the catalytic activity of CYP125 and CYP142 in vitro (K(I) values &lt; 0.1 muM), and rapidly depletes Mtb intracellular ATP (IC(50) = 0.15 muM). The compound has antimicrobial activity against both drug susceptible and MDR Mtb (MIC(99) values 0.4 - 1.5 muM) in extracellular assays, and inhibits the growth of Mtb in human macrophages (MIC = 1.7 muM) with good selectivity over mammalian cytotoxicity (LD(50) &gt;/= 50 muM). The combination of small molecule inhibitors and structural data reported here provide useful tools to study the role of cholesterol metabolism in Mtb and are a promising step towards novel antibiotics targeting bioenergetic pathways, which could be used to help combat MDR-TB.

Fragment-based development of small molecule inhibitors targeting Mycobacterium tuberculosis cholesterol metabolism.,Kavanagh ME, McLean KJ, Gilbert SH, Amadi C, Snee M, Tunnicliffe RB, Arora K, Boshoff HI, Fanourakis A, Rebello-Lopez MJ, Ortega-Muro F, Levy CW, Munro AW, Leys D, Abell C, Coyne AG bioRxiv [Preprint]. 2024 Dec 3:2024.10.28.620643. doi: 10.1101/2024.10.28.620643. PMID:39803573<ref>PMID:39803573</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8s53" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mycobacterium tuberculosis H37Rv]]
[[Category: Kavanagh M]]
[[Category: Levy C]]
[[Category: Leys D]]
[[Category: Snee M]]