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The | ==Crystal structure of compound C45 bound to the yeast 80S ribosome== | ||
<StructureSection load='6hhq' size='340' side='right'caption='[[6hhq]], [[Resolution|resolution]] 3.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6hhq]] is a 159 chain structure with sequence from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HHQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HHQ FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G5B:(3~{R})-3-[(1~{S})-2-[(1~{S},4~{a}~{R},6~{S},7~{S},8~{a}~{R})-6,7-bis(chloranyl)-5,5,8~{a}-trimethyl-2-methylidene-3,4,4~{a},6,7,8-hexahydro-1~{H}-naphthalen-1-yl]-1-oxidanyl-ethyl]pyrrolidine-2,5-dione'>G5B</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=OHX:OSMIUM+(III)+HEXAMMINE'>OHX</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6hhq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hhq OCA], [http://pdbe.org/6hhq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hhq RCSB], [http://www.ebi.ac.uk/pdbsum/6hhq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hhq ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/RS15_YEAST 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.<ref>PMID:15167894</ref> [[http://www.uniprot.org/uniprot/RL5_YEAST RL5_YEAST]] Binds 5S RNA and is required for 60S subunit assembly. [[http://www.uniprot.org/uniprot/GBLP_YEAST 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.<ref>PMID:15340087</ref> [[http://www.uniprot.org/uniprot/RL25_YEAST RL25_YEAST]] This protein binds to a specific region on the 26S rRNA. [[http://www.uniprot.org/uniprot/RS7A_YEAST RS7A_YEAST]] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.<ref>PMID:15590835</ref> [[http://www.uniprot.org/uniprot/RS9A_YEAST RS9A_YEAST]] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.<ref>PMID:15590835</ref> [[http://www.uniprot.org/uniprot/RSSA1_YEAST 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.<ref>PMID:9973221</ref> <ref>PMID:14627813</ref> [[http://www.uniprot.org/uniprot/RS2_YEAST 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.<ref>PMID:15590835</ref> [[http://www.uniprot.org/uniprot/RL40A_YEAST RL40A_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). 60S ribosomal protein L40-A: 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 (PubMed:22096102). eL40 is essential for translation of a subset of cellular transcripts, including stress response transcripts, such as DDR2 (PubMed:23169626).<ref>PMID:23169626</ref> <ref>PMID:22096102</ref> [[http://www.uniprot.org/uniprot/RS18A_YEAST 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] [[http://www.uniprot.org/uniprot/STM1_YEAST 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.<ref>PMID:15044472</ref> [[http://www.uniprot.org/uniprot/RS14B_YEAST RS14B_YEAST]] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.<ref>PMID:15590835</ref> [[http://www.uniprot.org/uniprot/RS6A_YEAST RS6A_YEAST]] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.<ref>PMID:15590835</ref> [[http://www.uniprot.org/uniprot/RS19A_YEAST 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.<ref>PMID:16159874</ref> <ref>PMID:17726054</ref> [[http://www.uniprot.org/uniprot/RS27A_YEAST 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). [[http://www.uniprot.org/uniprot/RS21A_YEAST 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.<ref>PMID:14627813</ref> [[http://www.uniprot.org/uniprot/RS31_YEAST RS31_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: 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.<ref>PMID:22096102</ref> [[http://www.uniprot.org/uniprot/RLA0_YEAST RLA0_YEAST]] Ribosomal protein P0 is the functional equivalent of E.coli protein L10. [[http://www.uniprot.org/uniprot/RL11B_YEAST RL11B_YEAST]] Binds to 5S ribosomal RNA. [[http://www.uniprot.org/uniprot/RL4A_YEAST RL4A_YEAST]] Participates in the regulation of the accumulation of its own mRNA.<ref>PMID:2065661</ref> [[http://www.uniprot.org/uniprot/RL37A_YEAST RL37A_YEAST]] Binds to the 23S rRNA (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Natural products that target the eukaryotic ribosome are promising therapeutics to treat a variety of cancers. It is therefore essential to determine their molecular mechanism of action to fully understand their mode of interaction with the target and to inform the development of new synthetic compounds with improved potency and reduced cytotoxicity. Toward this goal, we have previously established a short synthesis pathway that grants access to multiple congeners of the lissoclimide family. Here we present the X-ray co-crystal structure at 3.1 A resolution of C45, a potent congener with two A-ring chlorine-bearing stereogenic centers with 'unnatural' configurations, with the yeast 80S ribosome, intermolecular interaction energies of the C45/ribosome complex, and single-molecule FRET data quantifying the impact of C45 on both human and yeast ribosomes. Together, these data provide new insights into the role of unusual non-covalent halogen bonding interactions involved in the binding of this synthetic compound to the 80S ribosome. | |||
Understanding the role of intermolecular interactions between lissoclimides and the eukaryotic ribosome.,Pellegrino S, Meyer M, Konst ZA, Holm M, Voora VK, Kashinskaya D, Zanette C, Mobley DL, Yusupova G, Vanderwal CD, Blanchard SC, Yusupov M Nucleic Acids Res. 2019 Feb 13. pii: 5316741. doi: 10.1093/nar/gkz053. PMID:30759226<ref>PMID:30759226</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6hhq" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Saccharomyces cerevisiae]] | |||
[[Category: Pellegrino, S]] | |||
[[Category: Vanderwal, C D]] | |||
[[Category: Yusupov, M]] | [[Category: Yusupov, M]] | ||
[[Category: | [[Category: 80s ribosome]] | ||
[[Category: | [[Category: Anti-cancer]] | ||
[[Category: Inhibitor]] | |||
[[Category: Ribosome]] | |||