View source for 8y37


==Cryo-EM structure of Staphylococcus aureus (15B196) 50S ribosome in complex with MCX-190.==
<StructureSection load='8y37' size='340' side='right'caption='[[8y37]], [[Resolution|resolution]] 2.53&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8y37]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8Y37 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8Y37 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.53&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2MA:2-METHYLADENOSINE-5-MONOPHOSPHATE'>2MA</scene>, <scene name='pdbligand=2MG:2N-METHYLGUANOSINE-5-MONOPHOSPHATE'>2MG</scene>, <scene name='pdbligand=5MU:5-METHYLURIDINE+5-MONOPHOSPHATE'>5MU</scene>, <scene name='pdbligand=A1D6G:7-[4-[3-[[(1~{S},2~{R},5~{R},6~{S},7~{S},8~{R},9~{R},11~{R},13~{R},14~{R})-8-[(2~{S},3~{R},4~{S},6~{R})-4-(dimethylamino)-6-methyl-3-oxidanyl-oxan-2-yl]oxy-2-ethyl-9-methoxy-1,5,7,9,11,13-hexamethyl-4,12,16-tris(oxidanylidene)-3,17-dioxa-15-azabicyclo[12.3.0]heptadecan-6-yl]oxycarbonylamino]propoxy]but-1-ynyl]-1-methyl-4-oxidanylidene-quinoline-3-carboxylic+acid'>A1D6G</scene>, <scene name='pdbligand=MA6:6N-DIMETHYLADENOSINE-5-MONOPHOSHATE'>MA6</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=OMG:O2-METHYLGUANOSINE-5-MONOPHOSPHATE'>OMG</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=8y37 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8y37 OCA], [https://pdbe.org/8y37 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8y37 RCSB], [https://www.ebi.ac.uk/pdbsum/8y37 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8y37 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/RL35_STAAW RL35_STAAW] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Conventional macrolide-lincosamide-streptogramin B-ketolide (MLS(B)K) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLS(B)K in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like pi-pi stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLS(B)K antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLS(B)K antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance.

Synthetic macrolides overcoming MLS(B)K-resistant pathogens.,Ma CX, Li Y, Liu WT, Li Y, Zhao F, Lian XT, Ding J, Liu SM, Liu XP, Fan BZ, Liu LY, Xue F, Li J, Zhang JR, Xue Z, Pei XT, Lin JZ, Liang JH Cell Discov. 2024 Jul 11;10(1):75. doi: 10.1038/s41421-024-00702-y. PMID:38992047<ref>PMID:38992047</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8y37" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Staphylococcus aureus]]
[[Category: Li J]]
[[Category: Li Y]]
[[Category: Lin J]]
[[Category: Lu G]]
[[Category: Pei X]]