6i9r
From Proteopedia
Large subunit of the human mitochondrial ribosome in complex with Virginiamycin M and Quinupristin
Structural highlights
Disease[RM03_HUMAN] Combined oxidative phosphorylation defect type 9. The disease is caused by mutations affecting the gene represented in this entry. [RM44_HUMAN] Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency. The disease is caused by mutations affecting the gene represented in this entry. Function[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).[1] [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.[2] [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.[3] [4] [RM16_HUMAN] Component of the large subunit of mitochondrial ribosome. [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. [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.[5] [RM36_HUMAN] Component of the large subunit of the mitochondrial ribosome. Publication Abstract from PubMedGlioblastoma 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. 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[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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