6i9r

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<StructureSection load='6i9r' size='340' side='right'caption='[[6i9r]], [[Resolution|resolution]] 3.90&Aring;' scene=''>
<StructureSection load='6i9r' size='340' side='right'caption='[[6i9r]], [[Resolution|resolution]] 3.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6i9r]] is a 51 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I9R OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6I9R FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6i9r]] is a 51 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I9R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6I9R FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H8Q:~{N}-[(3~{S},6~{R},12~{R},15~{S},16~{S},19~{S},22~{S},25~{S})-25-[[(3~{S})-1-azabicyclo[2.2.2]octan-3-yl]sulfanylmethyl]-3-[[4-(dimethylamino)phenyl]methyl]-12-ethyl-4,16-dimethyl-2,5,11,14,18,21,24-heptakis(oxidanylidene)-19-phenyl-17-oxa-1,4,10,13,20-pentazatricyclo[20.4.0.0^{6,10}]hexacosan-15-yl]-3-oxidanyl-pyridine-2-carboxamide'>H8Q</scene>, <scene name='pdbligand=H8T:(10~{R},11~{R},12~{E},17~{E},19~{E},21~{S})-11,19-dimethyl-21-oxidanyl-10-propan-2-yl-9,26-dioxa-3,15,28-triazatricyclo[23.2.1.0^{3,7}]octacosa-1(27),4,6,12,17,19,25(28)-heptaene-2,8,14,23-tetrone'>H8T</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H8Q:~{N}-[(3~{S},6~{R},12~{R},15~{S},16~{S},19~{S},22~{S},25~{S})-25-[[(3~{S})-1-azabicyclo[2.2.2]octan-3-yl]sulfanylmethyl]-3-[[4-(dimethylamino)phenyl]methyl]-12-ethyl-4,16-dimethyl-2,5,11,14,18,21,24-heptakis(oxidanylidene)-19-phenyl-17-oxa-1,4,10,13,20-pentazatricyclo[20.4.0.0^{6,10}]hexacosan-15-yl]-3-oxidanyl-pyridine-2-carboxamide'>H8Q</scene>, <scene name='pdbligand=H8T:(10~{R},11~{R},12~{E},17~{E},19~{E},21~{S})-11,19-dimethyl-21-oxidanyl-10-propan-2-yl-9,26-dioxa-3,15,28-triazatricyclo[23.2.1.0^{3,7}]octacosa-1(27),4,6,12,17,19,25(28)-heptaene-2,8,14,23-tetrone'>H8T</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=2MA:2-METHYLADENOSINE-5-MONOPHOSPHATE'>2MA</scene>, <scene name='pdbligand=2MU:2,5-DIMETHYLURIDINE-5-MONOPHOSPHATE'>2MU</scene>, <scene name='pdbligand=5MC:5-METHYLCYTIDINE-5-MONOPHOSPHATE'>5MC</scene>, <scene name='pdbligand=5MU:5-METHYLURIDINE+5-MONOPHOSPHATE'>5MU</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=2MA:2-METHYLADENOSINE-5-MONOPHOSPHATE'>2MA</scene>, <scene name='pdbligand=2MU:2,5-DIMETHYLURIDINE-5-MONOPHOSPHATE'>2MU</scene>, <scene name='pdbligand=5MC:5-METHYLCYTIDINE-5-MONOPHOSPHATE'>5MC</scene>, <scene name='pdbligand=5MU:5-METHYLURIDINE+5-MONOPHOSPHATE'>5MU</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Aminoacyl-tRNA_hydrolase Aminoacyl-tRNA hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.29 3.1.1.29] </span></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Aminoacyl-tRNA_hydrolase Aminoacyl-tRNA hydrolase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.29 3.1.1.29] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6i9r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i9r OCA], [http://pdbe.org/6i9r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6i9r RCSB], [http://www.ebi.ac.uk/pdbsum/6i9r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6i9r ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6i9r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i9r OCA], [https://pdbe.org/6i9r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6i9r RCSB], [https://www.ebi.ac.uk/pdbsum/6i9r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6i9r ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/RM03_HUMAN RM03_HUMAN]] Combined oxidative phosphorylation defect type 9. The disease is caused by mutations affecting the gene represented in this entry. [[http://www.uniprot.org/uniprot/RM44_HUMAN RM44_HUMAN]] Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency. The disease is caused by mutations affecting the gene represented in this entry.
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[[https://www.uniprot.org/uniprot/RM03_HUMAN RM03_HUMAN]] Combined oxidative phosphorylation defect type 9. The disease is caused by mutations affecting the gene represented in this entry. [[https://www.uniprot.org/uniprot/RM44_HUMAN RM44_HUMAN]] Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency. The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/RM14_HUMAN RM14_HUMAN]] Forms part of 2 intersubunit bridges in the assembled ribosome. Upon binding to MALSU1 intersubunit bridge formation is blocked, preventing ribosome formation and repressing translation (Probable).<ref>PMID:22829778</ref> [[http://www.uniprot.org/uniprot/ICT1_HUMAN ICT1_HUMAN]] Essential peptidyl-tRNA hydrolase component of the mitochondrial large ribosomal subunit. Acts as a codon-independent translation release factor that has lost all stop codon specificity and directs the termination of translation in mitochondrion, possibly in case of abortive elongation. May be involved in the hydrolysis of peptidyl-tRNAs that have been prematurely terminated and thus in the recycling of stalled mitochondrial ribosomes.<ref>PMID:20186120</ref> [[http://www.uniprot.org/uniprot/RM41_HUMAN RM41_HUMAN]] Component of the mitochondrial ribosome large subunit. Also involved in apoptosis and cell cycle. Enhances p53/TP53 stability, thereby contributing to p53/TP53-induced apoptosis in response to growth-inhibitory condition. Enhances p53/TP53 translocation to the mitochondria. Has the ability to arrest the cell cycle at the G1 phase, possibly by stabilizing the CDKN1A and CDKN1B (p27Kip1) proteins.<ref>PMID:16024796</ref> <ref>PMID:16256947</ref> [[http://www.uniprot.org/uniprot/RM16_HUMAN RM16_HUMAN]] Component of the large subunit of mitochondrial ribosome. [[http://www.uniprot.org/uniprot/G45IP_HUMAN G45IP_HUMAN]] Acts as a negative regulator of G1 to S cell cycle phase progression by inhibiting cyclin-dependent kinases. Inhibitory effects are additive with GADD45 proteins but occurs also in the absence of GADD45 proteins. Acts as a repressor of the orphan nuclear receptor NR4A1 by inhibiting AB domain-mediated transcriptional activity. May be involved in the hormone-mediated regulation of NR4A1 transcriptional activity. May play a role in mitochondrial protein synthesis. [[http://www.uniprot.org/uniprot/RM44_HUMAN RM44_HUMAN]] Component of the 39S subunit of mitochondrial ribosome. May have a function in the assembly/stability of nascent mitochondrial polypeptides exiting the ribosome.<ref>PMID:23315540</ref> [[http://www.uniprot.org/uniprot/RM36_HUMAN RM36_HUMAN]] Component of the large subunit of the mitochondrial ribosome.
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[[https://www.uniprot.org/uniprot/RM14_HUMAN RM14_HUMAN]] Forms part of 2 intersubunit bridges in the assembled ribosome. Upon binding to MALSU1 intersubunit bridge formation is blocked, preventing ribosome formation and repressing translation (Probable).<ref>PMID:22829778</ref> [[https://www.uniprot.org/uniprot/ICT1_HUMAN ICT1_HUMAN]] Essential peptidyl-tRNA hydrolase component of the mitochondrial large ribosomal subunit. Acts as a codon-independent translation release factor that has lost all stop codon specificity and directs the termination of translation in mitochondrion, possibly in case of abortive elongation. May be involved in the hydrolysis of peptidyl-tRNAs that have been prematurely terminated and thus in the recycling of stalled mitochondrial ribosomes.<ref>PMID:20186120</ref> [[https://www.uniprot.org/uniprot/RM41_HUMAN RM41_HUMAN]] Component of the mitochondrial ribosome large subunit. Also involved in apoptosis and cell cycle. Enhances p53/TP53 stability, thereby contributing to p53/TP53-induced apoptosis in response to growth-inhibitory condition. Enhances p53/TP53 translocation to the mitochondria. Has the ability to arrest the cell cycle at the G1 phase, possibly by stabilizing the CDKN1A and CDKN1B (p27Kip1) proteins.<ref>PMID:16024796</ref> <ref>PMID:16256947</ref> [[https://www.uniprot.org/uniprot/RM16_HUMAN RM16_HUMAN]] Component of the large subunit of mitochondrial ribosome. [[https://www.uniprot.org/uniprot/G45IP_HUMAN G45IP_HUMAN]] Acts as a negative regulator of G1 to S cell cycle phase progression by inhibiting cyclin-dependent kinases. Inhibitory effects are additive with GADD45 proteins but occurs also in the absence of GADD45 proteins. Acts as a repressor of the orphan nuclear receptor NR4A1 by inhibiting AB domain-mediated transcriptional activity. May be involved in the hormone-mediated regulation of NR4A1 transcriptional activity. May play a role in mitochondrial protein synthesis. [[https://www.uniprot.org/uniprot/RM44_HUMAN RM44_HUMAN]] Component of the 39S subunit of mitochondrial ribosome. May have a function in the assembly/stability of nascent mitochondrial polypeptides exiting the ribosome.<ref>PMID:23315540</ref> [[https://www.uniprot.org/uniprot/RM36_HUMAN RM36_HUMAN]] Component of the large subunit of the mitochondrial ribosome.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Glioblastoma stem cells (GSCs) resist current glioblastoma (GBM) therapies. GSCs rely highly on oxidative phosphorylation (OXPHOS), whose function requires mitochondrial translation. Here we explore the therapeutic potential of targeting mitochondrial translation and report the results of high-content screening with putative blockers of mitochondrial ribosomes. We identify the bacterial antibiotic quinupristin/dalfopristin (Q/D) as an effective suppressor of GSC growth. Q/D also decreases the clonogenicity of GSCs in vitro, consequently dysregulating the cell cycle and inducing apoptosis. Cryoelectron microscopy (cryo-EM) reveals that Q/D binds to the large mitoribosomal subunit, inhibiting mitochondrial protein synthesis and functionally dysregulating OXPHOS complexes. These data suggest that targeting mitochondrial translation could be explored to therapeutically suppress GSC growth in GBM and that Q/D could potentially be repurposed for cancer treatment.
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Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth.,Sighel D, Notarangelo M, Aibara S, Re A, Ricci G, Guida M, Soldano A, Adami V, Ambrosini C, Broso F, Rosatti EF, Longhi S, Buccarelli M, D'Alessandris QG, Giannetti S, Pacioni S, Ricci-Vitiani L, Rorbach J, Pallini R, Roulland S, Amunts A, Mancini I, Modelska A, Quattrone A Cell Rep. 2021 Apr 27;35(4):109024. doi: 10.1016/j.celrep.2021.109024. PMID:33910005<ref>PMID:33910005</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6i9r" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>

Revision as of 10:39, 28 July 2021

Large subunit of the human mitochondrial ribosome in complex with Virginiamycin M and Quinupristin

PDB ID 6i9r

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