Details of Drug Off-Target (DOT)

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

• DOT Name: Small ribosomal subunit protein uS5 (RPS2)
• Synonyms: 40S ribosomal protein S2; 40S ribosomal protein S4; Protein LLRep3
• Gene Name: RPS2
• Related Disease:
  Advanced cancer
  Atrial fibrillation
  Classic Hodgkin lymphoma
  Melanoma
  Neoplasm
  Psoriatic arthritis
  Turner syndrome
  Familial atrial fibrillation
  Prostate neoplasm
  Colorectal carcinoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: RS2_HUMAN
• PDB ID: 4UG0 ; 4V6X ; 5A2Q ; 5AJ0 ; 5FLX ; 5LKS ; 5OA3 ; 5T2C ; 5VYC ; 6G18 ; 6G4S ; 6G51 ; 6G53 ; 6G5H ; 6G5I ; 6IP5 ; 6IP6 ; 6IP8 ; 6OLE ; 6OLF ; 6OLG ; 6OLI ; 6OLZ ; 6OM0 ; 6OM7 ; 6QZP ; 6XA1 ; 6Y0G ; 6Y2L ; 6Y57 ; 6YBD ; 6YBW ; 6Z6L ; 6Z6M ; 6Z6N ; 6ZLW ; 6ZM7 ; 6ZME ; 6ZMI ; 6ZMO ; 6ZMT ; 6ZMW ; 6ZN5 ; 6ZOJ ; 6ZOK ; 6ZON ; 6ZP4 ; 6ZUO ; 6ZV6 ; 6ZVH ; 6ZVJ ; 6ZXD ; 6ZXE ; 6ZXF ; 6ZXG ; 6ZXH ; 7A09 ; 7JQB ; 7JQC ; 7K5I ; 7QP6 ; 7QP7 ; 7QVP ; 7R4X ; 7TQL ; 7WTV ; 7WTW ; 7WTX ; 7WTZ ; 7WU0 ; 7XNX ; 7XNY ; 8G5Y ; 8G5Z ; 8G60 ; 8G61 ; 8G6J ; 8GLP ; 8JDJ ; 8JDK ; 8JDL ; 8JDM ; 8PPK ; 8PPL ; 8T4S
• Pfam ID: PF00333 ; PF03719
• Sequence:
  MADDAGAAGGPGGPGGPGMGNRGGFRGGFGSGIRGRGRGRGRGRGRGRGARGGKAEDKEW
  MPVTKLGRLVKDMKIKSLEEIYLFSLPIKESEIIDFFLGASLKDEVLKIMPVQKQTRAGQ
  RTRFKAFVAIGDYNGHVGLGVKCSKEVATAIRGAIILAKLSIVPVRRGYWGNKIGKPHTV
  PCKVTGRCGSVLVRLIPAPRGTGIVSAPVPKKLLMMAGIDDCYTSARGCTATLGNFAKAT
  FDAISKTYSYLTPDLWKETVFTKSPYQEFTDHLVKTHTRVSVQRTQAPAVATT
• 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. Plays a role in the assembly and function of the 40S ribosomal subunit. Mutations in this protein affects the control of translational fidelity. Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.
• 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)
  RMTs methylate histone arginines (R-HSA-3214858)
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  Translation initiation complex formation (R-HSA-72649)
  Formation of a pool of free 40S subunits (R-HSA-72689)
  Formation of the ternary complex, and subsequently, the 43S complex (R-HSA-72695)
  Ribosomal scanning and start codon recognition (R-HSA-72702)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  Eukaryotic Translation Termination (R-HSA-72764)
  Protein methylation (R-HSA-8876725)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Response of EIF2AK4 (GCN2) to amino acid deficiency (R-HSA-9633012)
  SARS-CoV-1 modulates host translation machinery (R-HSA-9735869)
  SARS-CoV-2 modulates host translation machinery (R-HSA-9754678)
  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

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[2]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[3]
Melanoma	DIS1RRCY	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Psoriatic arthritis	DISLWTG2	Strong	Biomarker	[5]
Turner syndrome	DIS2035C	Strong	Biomarker	[6]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[2]
Prostate neoplasm	DISHDKGQ	moderate	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Disputed	Biomarker	[8]
Prostate cancer	DISF190Y	Limited	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Small ribosomal subunit protein uS5 (RPS2).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Small ribosomal subunit protein uS5 (RPS2).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Small ribosomal subunit protein uS5 (RPS2).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Small ribosomal subunit protein uS5 (RPS2).	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Small ribosomal subunit protein uS5 (RPS2).	[13]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Small ribosomal subunit protein uS5 (RPS2).	[9]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Small ribosomal subunit protein uS5 (RPS2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Small ribosomal subunit protein uS5 (RPS2).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Small ribosomal subunit protein uS5 (RPS2).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Small ribosomal subunit protein uS5 (RPS2).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Small ribosomal subunit protein uS5 (RPS2).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Small ribosomal subunit protein uS5 (RPS2).	[21]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Small ribosomal subunit protein uS5 (RPS2).	[22]

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 Small ribosomal subunit protein uS5 (RPS2).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Small ribosomal subunit protein uS5 (RPS2).	[16]

References

• [1] RPS2: a novel therapeutic target in prostate cancer.J Exp Clin Cancer Res. 2009 Jan 12;28(1):6. doi: 10.1186/1756-9966-28-6.
• [2] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [3] Expression of housekeeping genes in Hodgkin's disease lymph nodes.Leukemia. 1991 Dec;5(12):1110-2.
• [4] Identification of robust reference genes for studies of gene expression in FFPE melanoma samples and melanoma cell lines.Melanoma Res. 2020 Feb;30(1):26-38. doi: 10.1097/CMR.0000000000000644.
• [5] Activatable Small-Molecule Photoacoustic Probes that Cross the Blood-Brain Barrier for Visualization of Copper(II) in Mice with Alzheimer's Disease.Angew Chem Int Ed Engl. 2019 Sep 2;58(36):12415-12419. doi: 10.1002/anie.201904047. Epub 2019 Aug 1.
• [6] Relationship between the monosomy X phenotype and Y-linked ribosomal protein S4 (Rps4) in several species of mammals: a molecular evolutionary analysis of Rps4 homologs.Genomics. 1996 Jan 1;31(1):44-50. doi: 10.1006/geno.1996.0007.
• [7] Role of ribosomal protein RPS2 in controlling let-7a expression in human prostate cancer.Mol Cancer Res. 2011 Jan;9(1):36-50. doi: 10.1158/1541-7786.MCR-10-0158. Epub 2010 Dec 8.
• [8] A genomic strategy for the functional validation of colorectal cancer genes identifies potential therapeutic targets.Int J Cancer. 2011 Mar 1;128(5):1069-79. doi: 10.1002/ijc.25453.
• [9] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [14] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [15] 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.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [18] Identification of formaldehyde-responsive genes by suppression subtractive hybridization. Toxicology. 2008 Jan 14;243(1-2):224-35.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [21] 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.
• [22] 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.