Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3VZ6OE)

• DOT Name: Large ribosomal subunit protein uL5 (RPL11)
• Synonyms: 60S ribosomal protein L11; CLL-associated antigen KW-12
• Gene Name: RPL11
• Related Disease:
  Advanced cancer
  Diamond-Blackfan anemia 1
  Diamond-Blackfan anemia 7
  Gastric cancer
  Herpes simplex infection
  Neoplasm
  Obesity
  Prostate cancer
  Prostate neoplasm
  Stomach cancer
  Diamond-Blackfan anemia
  Colorectal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Glioma
  Small lymphocytic lymphoma
• UniProt ID: RL11_HUMAN
• PDB ID: 4UG0 ; 4V6X ; 4XXB ; 5AJ0 ; 5LKS ; 5T2C ; 6IP5 ; 6IP6 ; 6IP8 ; 6LQM ; 6LSR ; 6LSS ; 6LU8 ; 6OLE ; 6OLF ; 6OLG ; 6OLI ; 6OLZ ; 6OM0 ; 6OM7 ; 6QZP ; 6W6L ; 6XA1 ; 6Y0G ; 6Y2L ; 6Y57 ; 6Y6X ; 6Z6L ; 6Z6M ; 6Z6N ; 6ZM7 ; 6ZME ; 6ZMI ; 6ZMO ; 7BHP ; 7F5S ; 7OW7 ; 7QVP ; 7XNX ; 7XNY ; 8A3D ; 8BGU ; 8FL0 ; 8FL2 ; 8FL3 ; 8FL4 ; 8FL6 ; 8FL7 ; 8FL9 ; 8FLA ; 8FLB ; 8FLC ; 8FLD ; 8FLE ; 8FLF ; 8G5Y ; 8G5Z ; 8G60 ; 8G61 ; 8G6J ; 8GLP ; 8IDT ; 8IDY ; 8IE3 ; 8INE ; 8INF ; 8INK ; 8IPD ; 8IPX ; 8IPY ; 8IR1 ; 8IR3 ; 8JDJ ; 8JDK ; 8JDL ; 8JDM
• Pfam ID: PF00281 ; PF00673
• Sequence:
  MAQDQGEKENPMRELRIRKLCLNICVGESGDRLTRAAKVLEQLTGQTPVFSKARYTVRSF
  GIRRNEKIAVHCTVRGAKAEEILEKGLKVREYELRKNNFSDTGNFGFGIQEHIDLGIKYD
  PSIGIYGLDFYVVLGRPGFSIADKKRRTGCIGAKHRISKEEAMRWFQQKYDGIILPGK
• Function: Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. The small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules. The large subunit (LSU) contains the ribosomal catalytic site termed the peptidyl transferase center (PTC), which catalyzes the formation of peptide bonds, thereby polymerizing the amino acids delivered by tRNAs into a polypeptide chain. The nascent polypeptides leave the ribosome through a tunnel in the LSU and interact with protein factors that function in enzymatic processing, targeting, and the membrane insertion of nascent chains at the exit of the ribosomal tunnel. As part of the 5S RNP/5S ribonucleoprotein particle it is an essential component of the LSU, required for its formation and the maturation of rRNAs. It also couples ribosome biogenesis to p53/TP53 activation. As part of the 5S RNP it accumulates in the nucleoplasm and inhibits MDM2, when ribosome biogenesis is perturbed, mediating the stabilization and the activation of TP53. Promotes nucleolar location of PML.
• KEGG Pathway:
  Ribosome (hsa03010)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Peptide chain elongation (R-HSA-156902)
  SRP-dependent cotranslational protein targeting to membrane (R-HSA-1799339)
  Viral mRNA Translation (R-HSA-192823)
  Selenocysteine synthesis (R-HSA-2408557)
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  Formation of a pool of free 40S subunits (R-HSA-72689)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  Eukaryotic Translation Termination (R-HSA-72764)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Response of EIF2AK4 (GCN2) to amino acid deficiency (R-HSA-9633012)
  Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) (R-HSA-975956)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Diamond-Blackfan anemia 1	DISP4NUV	Strong	Biomarker	[2]
Diamond-Blackfan anemia 7	DISK0CPA	Strong	Autosomal dominant	[3]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Obesity	DIS47Y1K	Strong	Biomarker	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[8]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
Diamond-Blackfan anemia	DISI2SNW	Supportive	Autosomal dominant	[9]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[10]
Endometrial cancer	DISW0LMR	Limited	Genetic Variation	[10]
Endometrial carcinoma	DISXR5CY	Limited	Genetic Variation	[10]
Glioma	DIS5RPEH	Limited	Biomarker	[10]
Small lymphocytic lymphoma	DIS30POX	Limited	Biomarker	[10]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Large ribosomal subunit protein uL5 (RPL11).	[11]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Large ribosomal subunit protein uL5 (RPL11).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Large ribosomal subunit protein uL5 (RPL11).	[14]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Large ribosomal subunit protein uL5 (RPL11).	[16]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Large ribosomal subunit protein uL5 (RPL11).	[17]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone affects the splicing of Large ribosomal subunit protein uL5 (RPL11).	[18]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Large ribosomal subunit protein uL5 (RPL11).	[19]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Large ribosomal subunit protein uL5 (RPL11).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Large ribosomal subunit protein uL5 (RPL11).	[15]

References

• [1] p53-Dependent Apoptotic Effect of Puromycin via Binding of Ribosomal Protein L5 and L11 to MDM2 and its Combination Effect with RITA or Doxorubicin.Cancers (Basel). 2019 Apr 24;11(4):582. doi: 10.3390/cancers11040582.
• [2] Assessment of hematopoietic failure due to Rpl11 deficiency in a zebrafish model of Diamond-Blackfan anemia by deep sequencing.BMC Genomics. 2013 Dec 17;14:896. doi: 10.1186/1471-2164-14-896.
• [3] Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet. 2008 Dec;83(6):769-80. doi: 10.1016/j.ajhg.2008.11.004.
• [4] PICT1 regulates TP53 via RPL11 and is involved in gastric cancer progression.Br J Cancer. 2013 Oct 15;109(8):2199-206. doi: 10.1038/bjc.2013.561. Epub 2013 Sep 17.
• [5] DNA sequence-specific ligands. XVII. Synthesis, spectral properties, virological and biochemical studies of fluorescent dimeric bisbenzimidazoles DBA(n).Bioorg Med Chem. 2018 May 15;26(9):2302-2309. doi: 10.1016/j.bmc.2018.03.018. Epub 2018 Mar 12.
• [6] GRWD1 negatively regulates p53 via the RPL11-MDM2 pathway and promotes tumorigenesis.EMBO Rep. 2017 Jan;18(1):123-137. doi: 10.15252/embr.201642444. Epub 2016 Nov 17.
• [7] Protection against High-Fat-Diet-Induced Obesity in MDM2(C305F) Mice Due to Reduced p53 Activity and Enhanced Energy Expenditure.Cell Rep. 2017 Jan 24;18(4):1005-1018. doi: 10.1016/j.celrep.2016.12.086.
• [8] Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.Nat Genet. 2018 May;50(5):682-692. doi: 10.1038/s41588-018-0086-z. Epub 2018 Apr 16.
• [9] Diamond-Blackfan Anemia. 2009 Jun 25 [updated 2023 Mar 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [10] Role of ribosomal protein mutations in tumor development (Review).Int J Oncol. 2016 Apr;48(4):1313-24. doi: 10.3892/ijo.2016.3387. Epub 2016 Feb 9.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [13] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [14] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [17] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [18] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.
• [19] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.