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The | ==Crystal structure of the wild-type Thermus thermophilus 70S ribosome in complex with tylosin, mRNA, deacylated A- and E-site tRNAphe, and deacylated P-site tRNAmet at 2.70A resolution== | ||
<StructureSection load='8g2d' size='340' side='right'caption='[[8g2d]], [[Resolution|resolution]] 2.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8g2d]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Thermus_thermophilus_HB8 Thermus thermophilus HB8]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8G2D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8G2D 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]] 2.7Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0TD:(3S)-3-(METHYLSULFANYL)-L-ASPARTIC+ACID'>0TD</scene>, <scene name='pdbligand=2MA:2-METHYLADENOSINE-5-MONOPHOSPHATE'>2MA</scene>, <scene name='pdbligand=2MG:2N-METHYLGUANOSINE-5-MONOPHOSPHATE'>2MG</scene>, <scene name='pdbligand=2MU:2,5-DIMETHYLURIDINE-5-MONOPHOSPHATE'>2MU</scene>, <scene name='pdbligand=4OC:4N,O2-METHYLCYTIDINE-5-MONOPHOSPHATE'>4OC</scene>, <scene name='pdbligand=4SU:4-THIOURIDINE-5-MONOPHOSPHATE'>4SU</scene>, <scene name='pdbligand=5MC:5-METHYLCYTIDINE-5-MONOPHOSPHATE'>5MC</scene>, <scene name='pdbligand=5MU:5-METHYLURIDINE+5-MONOPHOSPHATE'>5MU</scene>, <scene name='pdbligand=G7M:N7-METHYL-GUANOSINE-5-MONOPHOSPHATE'>G7M</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=M2G:N2-DIMETHYLGUANOSINE-5-MONOPHOSPHATE'>M2G</scene>, <scene name='pdbligand=MA6:6N-DIMETHYLADENOSINE-5-MONOPHOSHATE'>MA6</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MIA:2-METHYLTHIO-N6-ISOPENTENYL-ADENOSINE-5-MONOPHOSPHATE'>MIA</scene>, <scene name='pdbligand=OMC:O2-METHYLYCYTIDINE-5-MONOPHOSPHATE'>OMC</scene>, <scene name='pdbligand=OMG:O2-METHYLGUANOSINE-5-MONOPHOSPHATE'>OMG</scene>, <scene name='pdbligand=PSU:PSEUDOURIDINE-5-MONOPHOSPHATE'>PSU</scene>, <scene name='pdbligand=SF4:IRON/SULFUR+CLUSTER'>SF4</scene>, <scene name='pdbligand=TYK:TYLOSIN'>TYK</scene>, <scene name='pdbligand=UR3:3-METHYLURIDINE-5-MONOPHOSHATE'>UR3</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=8g2d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8g2d OCA], [https://pdbe.org/8g2d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8g2d RCSB], [https://www.ebi.ac.uk/pdbsum/8g2d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8g2d ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/RL15_THET8 RL15_THET8] Binds to the 23S rRNA (By similarity).[HAMAP-Rule:MF_01341_B] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The bacterial ribosome is an essential drug target as many clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent resistance mechanisms to PTC-acting drugs in Gram-positive bacteria is C8-methylation of the universally conserved A2503 nucleobase by Cfr methylase in 23S ribosomal RNA. Despite its clinical importance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. Here, we report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-transfer RNAs. These structures reveal an allosteric rearrangement of nucleotide A2062 upon Cfr-mediated methylation of A2503 that likely contributes to the reduced potency of some PTC inhibitors. Additionally, we provide the structural bases behind two distinct mechanisms of engaging the Cfr-methylated ribosome by the antibiotics iboxamycin and tylosin. | |||
Structural basis of Cfr-mediated antimicrobial resistance and mechanisms to evade it.,Aleksandrova EV, Wu KJY, Tresco BIC, Syroegin EA, Killeavy EE, Balasanyants SM, Svetlov MS, Gregory ST, Atkinson GC, Myers AG, Polikanov YS Nat Chem Biol. 2024 Jul;20(7):867-876. doi: 10.1038/s41589-023-01525-w. Epub 2024 , Jan 18. PMID:38238495<ref>PMID:38238495</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8g2d" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: Gregory | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Thermus thermophilus HB8]] | ||
[[Category: | [[Category: Aleksandrova EV]] | ||
[[Category: | [[Category: Atkinson GC]] | ||
[[Category: | [[Category: Balasanyants SM]] | ||
[[Category: | [[Category: Gregory ST]] | ||
[[Category: Killeavy EE]] | |||
[[Category: Myers AG]] | |||
[[Category: Polikanov YS]] | |||
[[Category: Svetlov MS]] | |||
[[Category: Syroegin EA]] | |||
[[Category: Tresco BIC]] | |||
[[Category: Wu KJY]] | |||
Latest revision as of 12:03, 14 July 2024
Crystal structure of the wild-type Thermus thermophilus 70S ribosome in complex with tylosin, mRNA, deacylated A- and E-site tRNAphe, and deacylated P-site tRNAmet at 2.70A resolutionCrystal structure of the wild-type Thermus thermophilus 70S ribosome in complex with tylosin, mRNA, deacylated A- and E-site tRNAphe, and deacylated P-site tRNAmet at 2.70A resolution
Structural highlights
FunctionRL15_THET8 Binds to the 23S rRNA (By similarity).[HAMAP-Rule:MF_01341_B] Publication Abstract from PubMedThe bacterial ribosome is an essential drug target as many clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent resistance mechanisms to PTC-acting drugs in Gram-positive bacteria is C8-methylation of the universally conserved A2503 nucleobase by Cfr methylase in 23S ribosomal RNA. Despite its clinical importance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. Here, we report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-transfer RNAs. These structures reveal an allosteric rearrangement of nucleotide A2062 upon Cfr-mediated methylation of A2503 that likely contributes to the reduced potency of some PTC inhibitors. Additionally, we provide the structural bases behind two distinct mechanisms of engaging the Cfr-methylated ribosome by the antibiotics iboxamycin and tylosin. Structural basis of Cfr-mediated antimicrobial resistance and mechanisms to evade it.,Aleksandrova EV, Wu KJY, Tresco BIC, Syroegin EA, Killeavy EE, Balasanyants SM, Svetlov MS, Gregory ST, Atkinson GC, Myers AG, Polikanov YS Nat Chem Biol. 2024 Jul;20(7):867-876. doi: 10.1038/s41589-023-01525-w. Epub 2024 , Jan 18. PMID:38238495[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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