6y6x
From Proteopedia
(Difference between revisions)
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==Tetracenomycin X bound to the human ribosome== | ==Tetracenomycin X bound to the human ribosome== | ||
| - | <StructureSection load='6y6x' size='340' side='right'caption='[[6y6x]]' scene=''> | + | <StructureSection load='6y6x' size='340' side='right'caption='[[6y6x]], [[Resolution|resolution]] 2.80Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Y6X OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Y6X FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6y6x]] is a 46 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=6Y6X OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Y6X FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6y6x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y6x OCA], [http://pdbe.org/6y6x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6y6x RCSB], [http://www.ebi.ac.uk/pdbsum/6y6x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6y6x ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=OCW:methyl+(6~{a}~{R},7~{S},10~{a}~{R})-3,8,10~{a}-trimethoxy-1-methyl-6~{a},7,12-tris(oxidanyl)-6,10,11-tris(oxidanylidene)-7~{H}-tetracene-2-carboxylate'>OCW</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6y6x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y6x OCA], [http://pdbe.org/6y6x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6y6x RCSB], [http://www.ebi.ac.uk/pdbsum/6y6x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6y6x ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/RL5_HUMAN RL5_HUMAN]] Blackfan-Diamond disease. Diamond-Blackfan anemia 6 (DBA6) [MIM:[http://omim.org/entry/612561 612561]]: A form of Diamond-Blackfan anemia, a congenital non-regenerative hypoplastic anemia that usually presents early in infancy. Diamond-Blackfan anemia is characterized by a moderate to severe macrocytic anemia, erythroblastopenia, and an increased risk of malignancy. 30 to 40% of Diamond-Blackfan anemia patients present with short stature and congenital anomalies, the most frequent being craniofacial (Pierre-Robin syndrome and cleft palate), thumb and urogenital anomalies. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:19061985</ref> <ref>PMID:19191325</ref> [[http://www.uniprot.org/uniprot/RL26_HUMAN RL26_HUMAN]] Diamond-Blackfan anemia 11 (DBA11) [MIM:[http://omim.org/entry/614900 614900]]: A form of Diamond-Blackfan anemia, a congenital non-regenerative hypoplastic anemia that usually presents early in infancy. Diamond-Blackfan anemia is characterized by a moderate to severe macrocytic anemia, erythroblastopenia, and an increased risk of malignancy. 30 to 40% of Diamond-Blackfan anemia patients present with short stature and congenital anomalies, the most frequent being craniofacial (Pierre-Robin syndrome and cleft palate), thumb and urogenital anomalies. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:22431104</ref> [[http://www.uniprot.org/uniprot/RL7A_HUMAN RL7A_HUMAN]] Note=Chromosomal recombination involving RPL7A activates the receptor kinase domain of the TRK oncogene. [[http://www.uniprot.org/uniprot/RL21_HUMAN RL21_HUMAN]] Hypotrichosis simplex. Note=Defects in RPL21 are a cause of generalized hypotrichosis simplex (HTS). A rare form of non-syndromic hereditary hypotrichosis without characteristic hair shaft anomalies. Affected individuals typically show normal hair at birth, but hair loss and thinning of the hair shaft start during early childhood and progress with age.<ref>PMID:21412954</ref> [[http://www.uniprot.org/uniprot/RL11_HUMAN RL11_HUMAN]] Blackfan-Diamond disease. Diamond-Blackfan anemia 7 (DBA7) [MIM:[http://omim.org/entry/612562 612562]]: A form of Diamond-Blackfan anemia, a congenital non-regenerative hypoplastic anemia that usually presents early in infancy. Diamond-Blackfan anemia is characterized by a moderate to severe macrocytic anemia, erythroblastopenia, and an increased risk of malignancy. 30 to 40% of Diamond-Blackfan anemia patients present with short stature and congenital anomalies, the most frequent being craniofacial (Pierre-Robin syndrome and cleft palate), thumb and urogenital anomalies. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:19061985</ref> <ref>PMID:19191325</ref> [[http://www.uniprot.org/uniprot/RL35A_HUMAN RL35A_HUMAN]] Blackfan-Diamond disease. Diamond-Blackfan anemia 5 (DBA5) [MIM:[http://omim.org/entry/612528 612528]]: A form of Diamond-Blackfan anemia, a congenital non-regenerative hypoplastic anemia that usually presents early in infancy. Diamond-Blackfan anemia is characterized by a moderate to severe macrocytic anemia, erythroblastopenia, and an increased risk of malignancy. 30 to 40% of Diamond-Blackfan anemia patients present with short stature and congenital anomalies, the most frequent being craniofacial (Pierre-Robin syndrome and cleft palate), thumb and urogenital anomalies. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:18535205</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/RL5_HUMAN RL5_HUMAN]] Required for rRNA maturation and formation of the 60S ribosomal subunits. This protein binds 5S RNA.<ref>PMID:19061985</ref> [[http://www.uniprot.org/uniprot/RL23A_HUMAN RL23A_HUMAN]] This protein binds to a specific region on the 26S rRNA (By similarity). [[http://www.uniprot.org/uniprot/RL13A_HUMAN RL13A_HUMAN]] Associated with ribosomes but is not required for canonical ribosome function and has extra-ribosomal functions. Component of the GAIT (gamma interferon-activated inhibitor of translation) complex which mediates interferon-gamma-induced transcript-selective translation inhibition in inflammation processes. Upon interferon-gamma activation and subsequent phosphorylation dissociates from the ribosome and assembles into the GAIT complex which binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin) and suppresses their translation. In the GAIT complex interacts with m7G cap-bound eIF4G at or near the eIF3-binding site and blocks the recruitment of the 43S ribosomal complex. Involved in methylation of rRNA.<ref>PMID:14567916</ref> <ref>PMID:17218275</ref> <ref>PMID:17921318</ref> <ref>PMID:23071094</ref> [[http://www.uniprot.org/uniprot/RL41_HUMAN RL41_HUMAN]] Interacts with the beta subunit of protein kinase CKII and stimulates phosphorylation of DNA topoisomerase II alpha by CKII. [[http://www.uniprot.org/uniprot/RL11_HUMAN RL11_HUMAN]] Binds to 5S ribosomal RNA (By similarity). Required for rRNA maturation and formation of the 60S ribosomal subunits. Promotes nucleolar location of PML (By similarity).<ref>PMID:19061985</ref> [[http://www.uniprot.org/uniprot/RL7_HUMAN RL7_HUMAN]] Binds to G-rich structures in 28S rRNA and in mRNAs. Plays a regulatory role in the translation apparatus; inhibits cell-free translation of mRNAs. [[http://www.uniprot.org/uniprot/RL40_HUMAN RL40_HUMAN]] 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, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. 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.<ref>PMID:16543144</ref> <ref>PMID:19754430</ref> Ribosomal protein L40 is a component of the 60S subunit of the ribosome.<ref>PMID:16543144</ref> <ref>PMID:19754430</ref> [[http://www.uniprot.org/uniprot/RL10L_HUMAN RL10L_HUMAN]] May play a role in compensating for the inactivated X-linked gene during spermatogenesis. [[http://www.uniprot.org/uniprot/RL37_HUMAN RL37_HUMAN]] Binds to the 23S rRNA (By similarity). [[http://www.uniprot.org/uniprot/RL6_HUMAN RL6_HUMAN]] Specifically binds to domain C of the Tax-responsive enhancer element in the long terminal repeat of HTLV-I. [[http://www.uniprot.org/uniprot/RL35A_HUMAN RL35A_HUMAN]] Required for the proliferation and viability of hematopoietic cells. Plays a role in 60S ribosomal subunit formation. The protein was found to bind to both initiator and elongator tRNAs and consequently was assigned to the P site or P and A site.<ref>PMID:18535205</ref> [[http://www.uniprot.org/uniprot/RL3_HUMAN RL3_HUMAN]] The L3 protein is a component of the large subunit of cytoplasmic ribosomes. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The increase in multi-drug resistant pathogenic bacteria is making our current arsenal of clinically used antibiotics obsolete, highlighting the urgent need for new lead compounds with distinct target binding sites to avoid cross-resistance. Here we report that the aromatic polyketide antibiotic tetracenomycin (TcmX) is a potent inhibitor of protein synthesis, and does not induce DNA damage as previously thought. Despite the structural similarity to the well-known translation inhibitor tetracycline, we show that TcmX does not interact with the small ribosomal subunit, but rather binds to the large subunit, within the polypeptide exit tunnel. This previously unappreciated binding site is located adjacent to the macrolide-binding site, where TcmX stacks on the noncanonical basepair formed by U1782 and U2586 of the 23S ribosomal RNA. Although the binding site is distinct from the macrolide antibiotics, our results indicate that like macrolides, TcmX allows translation of short oligopeptides before further translation is blocked. | ||
| + | |||
| + | Tetracenomycin X inhibits translation by binding within the ribosomal exit tunnel.,Osterman IA, Wieland M, Maviza TP, Lashkevich KA, Lukianov DA, Komarova ES, Zakalyukina YV, Buschauer R, Shiriaev DI, Leyn SA, Zlamal JE, Biryukov MV, Skvortsov DA, Tashlitsky VN, Polshakov VI, Cheng J, Polikanov YS, Bogdanov AA, Osterman AL, Dmitriev SE, Beckmann R, Dontsova OA, Wilson DN, Sergiev PV Nat Chem Biol. 2020 Jun 29. pii: 10.1038/s41589-020-0578-x. doi:, 10.1038/s41589-020-0578-x. PMID:32601485<ref>PMID:32601485</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6y6x" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Beckmann R]] | + | [[Category: Beckmann, R]] |
| - | [[Category: Berninghausen O]] | + | [[Category: Berninghausen, O]] |
| - | [[Category: Buschauer R]] | + | [[Category: Buschauer, R]] |
| - | [[Category: Cheng J]] | + | [[Category: Cheng, J]] |
| - | [[Category: Wilson | + | [[Category: Wilson, D N]] |
| + | [[Category: Antibiotic]] | ||
| + | [[Category: Translation inhibitor]] | ||
Revision as of 07:48, 30 September 2020
Tetracenomycin X bound to the human ribosome
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