| Structural highlights
5mei is a 159 chain structure with sequence from [1] and Baker's yeast. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , |
| NonStd Res: | |
| Gene: | RPL8A, MAK7, RPL4A, YHL033C (Baker's yeast), RPL9A, RPL8A, RPL9, YGL147C (Baker's yeast), RPL10, GRC5, QSR1, YLR075W (Baker's yeast), RPL11B, RP39B, RPL16B, YGR085C (Baker's yeast), RPL13A, YDL082W (Baker's yeast), RPL14A, YKL006W, YKL153 (Baker's yeast), RPL15A, RPL10A, RPL13A, YL10A, YLR029C (Baker's yeast), RPL16A, RPL13, RPL21A, YIL133C (Baker's yeast), RPL17A, RPL17, RPL20A, YKL180W (Baker's yeast), RPL18A, RP28A, YOL120C (Baker's yeast), RPL19A, RPL23A, YL14A, YBR084C-A, YBR084BC (Baker's yeast), RPL20A, RPL18A, RPL18A2, YMR242C, YM9408.04C (Baker's yeast), RPL21A, URP1, YBR191W, YBR1401 (Baker's yeast), RPL22A, YLR061W, L2168 (Baker's yeast), RPL23A, RPL17A, RPL17AA, YBL087C, YBL0713 (Baker's yeast), RPL24A, RP29, RPL30A, YGL031C (Baker's yeast), RPL25, YOL127W (Baker's yeast), RPL26A, RPL26, RPL33A, YLR344W, L8300.4 (Baker's yeast), RPL27A, RPL27, YHR010W (Baker's yeast), RPL28, CYH2, YGL103W (Baker's yeast), RPL29, YL43, YFR032C-A, YFR032BW (Baker's yeast), RPL30, RPL32, YGL030W (Baker's yeast), RPL31A, RPL34, RPL34A, YDL075W, D2478 (Baker's yeast), RPL32, YBL092W, YBL0838 (Baker's yeast), RPL33A, RPL37A, YPL143W, LPI4W, P2625 (Baker's yeast), RPL34A, YER056C-A, YER056BC (Baker's yeast), RPL35A, SOS1, YDL191W, D1249 (Baker's yeast), RPL36A, RPL39A, YMR194W, YM9646.06 (Baker's yeast), RPL37A, RPL35A, YLR185W, L9470.6 (Baker's yeast), RPL2A, RPL5B, YFR031C-A, YFR031BC (Baker's yeast), RPL38, YLR325C, L8543.2 (Baker's yeast), RPL39, RPL46, SPB2, YJL189W, J0360 (Baker's yeast), RPL40A, UBI1, YIL148W (Baker's yeast), RPL41B, RPL47B, YL41B, YDL133C-A, YDL133BC (Baker's yeast), RPL42A, RPL41A, SCL41A, YNL162W, N1722 (Baker's yeast), RPL43A, YPR043W, YP9499.02 (Baker's yeast), STM1, MPT4, STO1, YLR150W, L9634.1 (Baker's yeast), RPP0, L10E, RPA0, RPL10E, RPLA0, YLR340W, L8300.8 (Baker's yeast), RPS0A, NAB1, NAB1A, YST1, YGR214W (Baker's yeast), RPL3, MAK8, TCM1, YOR063W, YOR29-14 (Baker's yeast), RPS1A, PLC1, RPS10A, YLR441C, L9753.9 (Baker's yeast), RPS2, RPS4, SUP38, SUP44, YGL123W, G2893 (Baker's yeast), RPS3, SUF14, YNL178W, N1653 (Baker's yeast), RPS4A, RPS7B, YJR145C, J2186 (Baker's yeast), RPS5, RPS2, YJR123W, J2045 (Baker's yeast), RPS6A, RPS101, RPS10B, YPL090C, LPG18C (Baker's yeast), RPS7A, RPS30, YOR096W, YOR3177W (Baker's yeast), RPS8A, RPS14A, YBL072C, YBL06.05, YBL0613 (Baker's yeast), RPS9A, RPS13A, YS11A, YPL081W (Baker's yeast), RPS10A, YOR293W (Baker's yeast), RPL4A, RPL2, RPL2A, YBR031W, YBR0315 (Baker's yeast), RPS11A, RPS18A, YDR025W, YD9813.03 (Baker's yeast), RPS12, YOR369C (Baker's yeast), RPS13, RPS13C, YDR064W, D4252, YD9609.18 (Baker's yeast), RPS14B, CRY2, YJL191W, J0354 (Baker's yeast), RPS15, RPS21, YOL040C (Baker's yeast), RPS16A, RP61R, YMR143W, YM9375.12 (Baker's yeast), RPS17B, RP51B, YDR447C (Baker's yeast), RPS18A, YDR450W, D9461.35 (Baker's yeast), RPS19A, RP55A, RPS16AA, YOL121C (Baker's yeast), RPS20, URP2, YHL015W (Baker's yeast), RPL5, RPL1, RPL1A, YPL131W, LPI14W (Baker's yeast), RPS21A, RPS25, RPS25A, RPS26A, YKR057W (Baker's yeast), RPS22A, RPS24, RPS24A, YJL190C, J0355 (Baker's yeast), RPS23A, RPS28A, YGR118W, G6178 (Baker's yeast), RPS24A, RPS24EA, YER074W (Baker's yeast), RPS25A, RPS31A, YGR027C (Baker's yeast), RPS26B, YER131W (Baker's yeast), RPS27A, YKL156W (Baker's yeast), RPS28A, RPS33, RPS33A, YOR167C, O3600 (Baker's yeast), RPS29A, RPS36A, YS29A, YLR388W, L8084.11 (Baker's yeast), RPS30A, YLR287C-A, L8003.23, YLR287BC (Baker's yeast), RPL6A, RPL17A, YL16A, YML073C (Baker's yeast), RPS31, RPS37, UBI3, YLR167W, L9470.14 (Baker's yeast), ASC1, CPC2, YMR116C, YM9718.15C (Baker's yeast), RPS17A, RP51A, YML024W (Baker's yeast), RPL7A, RPL6A, RPL8A, YL8A, YGL076C (Baker's yeast) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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Function
[RS14B_YEAST] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.[1] [RL5_YEAST] Binds 5S RNA and is required for 60S subunit assembly. [RS27A_YEAST] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, and DNA-damage responses. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling (By similarity). 40S ribosomal protein S31 is a component of the 40S subunit of the ribosome (By similarity). [RS6A_YEAST] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.[2] [RL25_YEAST] This protein binds to a specific region on the 26S rRNA. [STM1_YEAST] Binds specifically G4 quadruplex (these are four-stranded right-handed helices, stabilized by guanine base quartets) and purine motif triplex (characterized by a third, antiparallel purine-rich DNA strand located within the major groove of a homopurine stretch of duplex DNA) nucleic acid structures. These structures may be present at telomeres or in rRNAs. Acts with CDC13 to control telomere length homeostasis. Involved in the control of the apoptosis-like cell death.[3] [RL37A_YEAST] Binds to the 23S rRNA (By similarity). [RS15_YEAST] Involved in the nuclear export of the small ribosomal subunit. Has a role in the late stage of the assembly of pre-40S particles within the nucleus and controls their export to the cytoplasm.[4] [RS9A_YEAST] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.[5] [GBLP_YEAST] Located at the head of the 40S ribosomal subunit in the vicinity of the mRNA exit channel, it serves as a scaffold protein that can recruit other proteins to the ribosome. Involved in the negative regulation of translation of a specific subset of proteins.[6] [RS7A_YEAST] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.[7] [RS18A_YEAST] Located at the top of the head of the 40S subunit, it contacts several helices of the 18S rRNA (By similarity).[HAMAP-Rule:MF_01315] [RS21A_YEAST] Required for the processing of the 20S rRNA-precursor to mature 18S rRNA in a late step of the maturation of 40S ribosomal subunits. Has a physiological role leading to 18S rRNA stability.[8] [RS19A_YEAST] Required for proper maturation of the small (40S) ribosomal subunit. Binds to 40s pre-ribosomal particles, probably required after association of NOC4 but before association of ENP1, TSR1 and RIO2 with 20/21S pre-rRNA.[9] [10] [RSSA1_YEAST] Required for the assembly and/or stability of the 40S ribosomal subunit. Required for the processing of the 20S rRNA-precursor to mature 18S rRNA in a late step of the maturation of 40S ribosomal subunits.[11] [12] [RL401_YEAST] Ubiquitin: exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, and DNA-damage responses. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling (By similarity).[13] 60S ribosomal protein L40: component of the 60S subunit of the ribosome. Ribosomal protein L40 is essential for translation of a subset of cellular transcripts, including stress response transcripts, such as DDR2.[14] [RL11B_YEAST] Binds to 5S ribosomal RNA. [RL4A_YEAST] Participates in the regulation of the accumulation of its own mRNA.[15] [RS2_YEAST] Important 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.[16] [RLA0_YEAST] Ribosomal protein P0 is the functional equivalent of E.coli protein L10.
Publication Abstract from PubMed
Protein synthesis plays an essential role in cell proliferation, differentiation, and survival. Inhibitors of eukaryotic translation have entered the clinic, establishing the translation machinery as a promising target for chemotherapy. A recently discovered, structurally unique marine sponge-derived brominated alkaloid, (-)-agelastatin A (AglA), possesses potent antitumor activity. Its underlying mechanism of action, however, has remained unknown. Using a systematic top-down approach, we show that AglA selectively inhibits protein synthesis. Using a high-throughput chemical footprinting method, we mapped the AglA-binding site to the ribosomal A site. A 3.5 A crystal structure of the 80S eukaryotic ribosome from S. cerevisiae in complex with AglA was obtained, revealing multiple conformational changes of the nucleotide bases in the ribosome accompanying the binding of AglA. Together, these results have unraveled the mechanism of inhibition of eukaryotic translation by AglA at atomic level, paving the way for future structural modifications to develop AglA analogs into novel anticancer agents.
Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A.,McClary B, Zinshteyn B, Meyer M, Jouanneau M, Pellegrino S, Yusupova G, Schuller A, Reyes JCP, Lu J, Guo Z, Ayinde S, Luo C, Dang Y, Romo D, Yusupov M, Green R, Liu JO Cell Chem Biol. 2017 May 18;24(5):605-613.e5. doi:, 10.1016/j.chembiol.2017.04.006. Epub 2017 Apr 27. PMID:28457705[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bernstein KA, Gallagher JE, Mitchell BM, Granneman S, Baserga SJ. The small-subunit processome is a ribosome assembly intermediate. Eukaryot Cell. 2004 Dec;3(6):1619-26. PMID:15590835 doi:http://dx.doi.org/10.1128/EC.3.6.1619-1626.2004
- ↑ Bernstein KA, Gallagher JE, Mitchell BM, Granneman S, Baserga SJ. The small-subunit processome is a ribosome assembly intermediate. Eukaryot Cell. 2004 Dec;3(6):1619-26. PMID:15590835 doi:http://dx.doi.org/10.1128/EC.3.6.1619-1626.2004
- ↑ Van Dyke MW, Nelson LD, Weilbaecher RG, Mehta DV. Stm1p, a G4 quadruplex and purine motif triplex nucleic acid-binding protein, interacts with ribosomes and subtelomeric Y' DNA in Saccharomyces cerevisiae. J Biol Chem. 2004 Jun 4;279(23):24323-33. Epub 2004 Mar 23. PMID:15044472 doi:http://dx.doi.org/10.1074/jbc.M401981200
- ↑ Leger-Silvestre I, Milkereit P, Ferreira-Cerca S, Saveanu C, Rousselle JC, Choesmel V, Guinefoleau C, Gas N, Gleizes PE. The ribosomal protein Rps15p is required for nuclear exit of the 40S subunit precursors in yeast. EMBO J. 2004 Jun 16;23(12):2336-47. Epub 2004 May 27. PMID:15167894 doi:http://dx.doi.org/10.1038/sj.emboj.7600252
- ↑ Bernstein KA, Gallagher JE, Mitchell BM, Granneman S, Baserga SJ. The small-subunit processome is a ribosome assembly intermediate. Eukaryot Cell. 2004 Dec;3(6):1619-26. PMID:15590835 doi:http://dx.doi.org/10.1128/EC.3.6.1619-1626.2004
- ↑ Gerbasi VR, Weaver CM, Hill S, Friedman DB, Link AJ. Yeast Asc1p and mammalian RACK1 are functionally orthologous core 40S ribosomal proteins that repress gene expression. Mol Cell Biol. 2004 Sep;24(18):8276-87. PMID:15340087 doi:10.1128/MCB.24.18.8276-8287.2004
- ↑ Bernstein KA, Gallagher JE, Mitchell BM, Granneman S, Baserga SJ. The small-subunit processome is a ribosome assembly intermediate. Eukaryot Cell. 2004 Dec;3(6):1619-26. PMID:15590835 doi:http://dx.doi.org/10.1128/EC.3.6.1619-1626.2004
- ↑ Tabb-Massey A, Caffrey JM, Logsden P, Taylor S, Trent JO, Ellis SR. Ribosomal proteins Rps0 and Rps21 of Saccharomyces cerevisiae have overlapping functions in the maturation of the 3' end of 18S rRNA. Nucleic Acids Res. 2003 Dec 1;31(23):6798-805. PMID:14627813
- ↑ Leger-Silvestre I, Caffrey JM, Dawaliby R, Alvarez-Arias DA, Gas N, Bertolone SJ, Gleizes PE, Ellis SR. Specific Role for Yeast Homologs of the Diamond Blackfan Anemia-associated Rps19 Protein in Ribosome Synthesis. J Biol Chem. 2005 Nov 18;280(46):38177-85. Epub 2005 Sep 12. PMID:16159874 doi:http://dx.doi.org/10.1074/jbc.M506916200
- ↑ Gregory LA, Aguissa-Toure AH, Pinaud N, Legrand P, Gleizes PE, Fribourg S. Molecular basis of Diamond-Blackfan anemia: structure and function analysis of RPS19. Nucleic Acids Res. 2007;35(17):5913-21. Epub 2007 Aug 28. PMID:17726054 doi:10.1093/nar/gkm626
- ↑ Ford CL, Randal-Whitis L, Ellis SR. Yeast proteins related to the p40/laminin receptor precursor are required for 20S ribosomal RNA processing and the maturation of 40S ribosomal subunits. Cancer Res. 1999 Feb 1;59(3):704-10. PMID:9973221
- ↑ Tabb-Massey A, Caffrey JM, Logsden P, Taylor S, Trent JO, Ellis SR. Ribosomal proteins Rps0 and Rps21 of Saccharomyces cerevisiae have overlapping functions in the maturation of the 3' end of 18S rRNA. Nucleic Acids Res. 2003 Dec 1;31(23):6798-805. PMID:14627813
- ↑ Lee AS, Burdeinick-Kerr R, Whelan SP. A ribosome-specialized translation initiation pathway is required for cap-dependent translation of vesicular stomatitis virus mRNAs. Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):324-9. doi: 10.1073/pnas.1216454109. , Epub 2012 Nov 19. PMID:23169626 doi:http://dx.doi.org/10.1073/pnas.1216454109
- ↑ Lee AS, Burdeinick-Kerr R, Whelan SP. A ribosome-specialized translation initiation pathway is required for cap-dependent translation of vesicular stomatitis virus mRNAs. Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):324-9. doi: 10.1073/pnas.1216454109. , Epub 2012 Nov 19. PMID:23169626 doi:http://dx.doi.org/10.1073/pnas.1216454109
- ↑ Presutti C, Ciafre SA, Bozzoni I. The ribosomal protein L2 in S. cerevisiae controls the level of accumulation of its own mRNA. EMBO J. 1991 Aug;10(8):2215-21. PMID:2065661
- ↑ Bernstein KA, Gallagher JE, Mitchell BM, Granneman S, Baserga SJ. The small-subunit processome is a ribosome assembly intermediate. Eukaryot Cell. 2004 Dec;3(6):1619-26. PMID:15590835 doi:http://dx.doi.org/10.1128/EC.3.6.1619-1626.2004
- ↑ McClary B, Zinshteyn B, Meyer M, Jouanneau M, Pellegrino S, Yusupova G, Schuller A, Reyes JCP, Lu J, Guo Z, Ayinde S, Luo C, Dang Y, Romo D, Yusupov M, Green R, Liu JO. Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A. Cell Chem Biol. 2017 May 18;24(5):605-613.e5. doi:, 10.1016/j.chembiol.2017.04.006. Epub 2017 Apr 27. PMID:28457705 doi:http://dx.doi.org/10.1016/j.chembiol.2017.04.006
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