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==COMPLEX OF THE LARGE RIBOSOMAL SUBUNIT FROM DEINOCOCCUS RADIODURANS WITH QUINUPRISTIN AND DALFOPRISTIN==
==COMPLEX OF THE LARGE RIBOSOMAL SUBUNIT FROM DEINOCOCCUS RADIODURANS WITH QUINUPRISTIN AND DALFOPRISTIN==
<StructureSection load='1sm1' size='340' side='right' caption='[[1sm1]], [[Resolution|resolution]] 3.42&Aring;' scene=''>
<StructureSection load='1sm1' size='340' side='right'caption='[[1sm1]], [[Resolution|resolution]] 3.42&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1sm1]] is a 31 chain structure with sequence from [http://en.wikipedia.org/wiki/Deinococcus_radiodurans Deinococcus radiodurans]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SM1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1SM1 FirstGlance]. <br>
<table><tr><td colspan='2'>[[1sm1]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Deinococcus_radiodurans Deinococcus radiodurans] and [https://en.wikipedia.org/wiki/Streptomyces_graminofaciens Streptomyces graminofaciens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SM1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1SM1 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DOL:5-(2-DIETHYLAMINO-ETHANESULFONYL)-21-HYDROXY-10-ISOPROPYL-11,19-DIMETHYL-9,26-DIOXA-3,15,28-TRIAZA-TRICYCLO[23.2.1.00,255]OCTACOSA-1(27),12,17,19,25(28)-PENTAENE-2,8,14,23-TETRAONE'>DOL</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.42&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=004:(2S)-AMINO(PHENYL)ETHANOIC+ACID'>004</scene>, <scene name='pdbligand=DBB:D-ALPHA-AMINOBUTYRIC+ACID'>DBB</scene>, <scene name='pdbligand=MHT:(3S)-3-(METHYLSULFANYL)-1-AZABICYCLO[2.2.2]OCTANE'>MHT</scene>, <scene name='pdbligand=MHU:4-N,N-(DIMETHYLAMINO)-L-PHENYLALANINE'>MHU</scene>, <scene name='pdbligand=MHV:4-OXO-L-PIPECOLIC+ACID'>MHV</scene>, <scene name='pdbligand=MHW:3-HYDROXYPICOLINIC+ACID'>MHW</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=004:(2S)-AMINO(PHENYL)ETHANOIC+ACID'>004</scene>, <scene name='pdbligand=DBB:D-ALPHA-AMINOBUTYRIC+ACID'>DBB</scene>, <scene name='pdbligand=DOL:5-(2-DIETHYLAMINO-ETHANESULFONYL)-21-HYDROXY-10-ISOPROPYL-11,19-DIMETHYL-9,26-DIOXA-3,15,28-TRIAZA-TRICYCLO[23.2.1.00,255]OCTACOSA-1(27),12,17,19,25(28)-PENTAENE-2,8,14,23-TETRAONE'>DOL</scene>, <scene name='pdbligand=MHT:(3S)-3-(METHYLSULFANYL)-1-AZABICYCLO[2.2.2]OCTANE'>MHT</scene>, <scene name='pdbligand=MHU:4-N,N-(DIMETHYLAMINO)-L-PHENYLALANINE'>MHU</scene>, <scene name='pdbligand=MHV:4-OXO-L-PIPECOLIC+ACID'>MHV</scene>, <scene name='pdbligand=MHW:3-HYDROXYPICOLINIC+ACID'>MHW</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=1sm1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1sm1 OCA], [http://pdbe.org/1sm1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1sm1 RCSB], [http://www.ebi.ac.uk/pdbsum/1sm1 PDBsum]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1sm1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1sm1 OCA], [https://pdbe.org/1sm1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1sm1 RCSB], [https://www.ebi.ac.uk/pdbsum/1sm1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1sm1 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/RL32_DEIRA RL32_DEIRA]] Forms a cluster with L17 and L22, and with L22, a pair of "tweezers" that hold together all the domains of the 23S rRNA. Interacts with the antibiotic troleandomycin which blocks the peptide exit tunnel.[HAMAP-Rule:MF_00340] [[http://www.uniprot.org/uniprot/RL5_DEIRA RL5_DEIRA]] This is 1 of the proteins that binds and probably mediates the attachment of the 5S RNA into the large ribosomal subunit, where it forms part of the central protuberance. In the 70S ribosome it contacts protein S13 of the 30S subunit (bridge B1b), connecting the 2 subunits; this bridge is implicated in subunit movement (By similarity). Contacts the P site tRNA; the 5S rRNA and some of its associated proteins might help stabilize positioning of ribosome-bound tRNAs.[HAMAP-Rule:MF_01333_B] [[http://www.uniprot.org/uniprot/RL19_DEIRA RL19_DEIRA]] This protein is located at the 30S-50S ribosomal subunit interface and may play a role in the structure and function of the aminoacyl-tRNA binding site (By similarity). Binds the 23S rRNA.[HAMAP-Rule:MF_00402] [[http://www.uniprot.org/uniprot/RL24_DEIRA RL24_DEIRA]] One of two assembly initiator proteins, it binds directly to the 5'-end of the 23S rRNA, where it nucleates assembly of the 50S subunit (By similarity).[HAMAP-Rule:MF_01326_B]  One of the proteins that surrounds the polypeptide exit tunnel on the outside of the subunit. Contacts trigger factor (TF) when it is bound to the ribosome; this contact may expose a hydrophobic crevice in TF (PubMed:16271892).[HAMAP-Rule:MF_01326_B] [[http://www.uniprot.org/uniprot/RL33_DEIRA RL33_DEIRA]] Binds the 23S rRNA and the E site tRNA.[HAMAP-Rule:MF_00294] [[http://www.uniprot.org/uniprot/RL15_DEIRA RL15_DEIRA]] Binds to the 23S rRNA.[HAMAP-Rule:MF_01341_B] [[http://www.uniprot.org/uniprot/RL20_DEIRA RL20_DEIRA]] Binds directly to 23S rRNA, probably serving to organize its structure.[HAMAP-Rule:MF_00382] [[http://www.uniprot.org/uniprot/RL16_DEIRA RL16_DEIRA]] Binds the 5S and 23S rRNAs and is also seen to make contacts with the A and P site tRNAs. Interacts with A site tRNA mimics, and is probably one of the key factors, along with a helix of the 23S rRNA, in positioning tRNA stems in the peptidyl-transferase center.[HAMAP-Rule:MF_01342] [[http://www.uniprot.org/uniprot/RL30_DEIRA RL30_DEIRA]] Binds the 5S and 23S rRNAs.[HAMAP-Rule:MF_01371] [[http://www.uniprot.org/uniprot/RL21_DEIRA RL21_DEIRA]] Binds directly to 23S rRNA, probably serving to organize its structure.[HAMAP-Rule:MF_01363] [[http://www.uniprot.org/uniprot/RL9_DEIRA RL9_DEIRA]] Binds to the 23S rRNA and protein L31.[HAMAP-Rule:MF_00503] [[http://www.uniprot.org/uniprot/RL14_DEIRA RL14_DEIRA]] Forms part of two intersubunit bridges in the 70S ribosome (By similarity). Binds to 23S rRNA.[HAMAP-Rule:MF_01367] [[http://www.uniprot.org/uniprot/RL29_DEIRA RL29_DEIRA]] Binds the 23S rRNA. One of the proteins that surrounds the polypeptide exit tunnel on the outside of the subunit.[HAMAP-Rule:MF_00374] [[http://www.uniprot.org/uniprot/RL25_DEIRA RL25_DEIRA]] This is one of 3 proteins that mediate the attachment of the 5S rRNA onto the large ribosomal subunit. This protein has three domains. The N-terminal one is bound on the solvent face, the middle domain fills the space between the 5S rRNA and the L11 arm contacting the 23S rRNA while the C-terminal domain is on the edge of the intersubunit interface and contacts the A site. The protein conformation changes upon binding of a tRNA mimic to the A site, although the mimic does not interact directly with CTC itself, consistent with CTCs presumed role in moderating A site binding.[HAMAP-Rule:MF_01334] [[http://www.uniprot.org/uniprot/RL23_DEIRA RL23_DEIRA]] One of the early assembly protein (By similarity) it binds 23S rRNA. One of the proteins that surrounds the polypeptide exit tunnel on the outside of the subunit. Forms the main docking site for trigger factor binding to the ribosome (PubMed:16091460 and PubMed:16271892).[HAMAP-Rule:MF_01369] [[http://www.uniprot.org/uniprot/RL27_DEIRA RL27_DEIRA]] Binds the 5S and 23S rRNAs and also the tRNA in the P site.[HAMAP-Rule:MF_00539] [[http://www.uniprot.org/uniprot/RL34_DEIRA RL34_DEIRA]] Binds the 23S rRNA.[HAMAP-Rule:MF_00391] [[http://www.uniprot.org/uniprot/RL3_DEIRA RL3_DEIRA]] One of the primary rRNA binding proteins, it binds directly near the 3'-end of the 23S rRNA, where it nucleates assembly of the 50S subunit (By similarity).[HAMAP-Rule:MF_01325_B] [[http://www.uniprot.org/uniprot/RL6_DEIRA RL6_DEIRA]] It is located near the subunit interface in the base of the L7/L12 stalk, and near the tRNA binding site of the peptidyltransferase center (By similarity). This protein binds to the 23S rRNA, and is important in its secondary structure.[HAMAP-Rule:MF_01365] [[http://www.uniprot.org/uniprot/RL11_DEIRA RL11_DEIRA]] This protein binds directly to 23S ribosomal RNA and also contacts the CTC protein (RL25).[HAMAP-Rule:MF_00736_B] [[http://www.uniprot.org/uniprot/RL13_DEIRA RL13_DEIRA]] This protein is one of the early assembly proteins of the 50S ribosomal subunit (By similarity). Binds to the 23S rRNA.[HAMAP-Rule:MF_01366_B] [[http://www.uniprot.org/uniprot/RL18_DEIRA RL18_DEIRA]] This is one of the proteins that binds and mediates the attachment of the 5S RNA into the large ribosomal subunit, where it forms part of the central protuberance.[HAMAP-Rule:MF_01337_B] [[http://www.uniprot.org/uniprot/RL2_DEIRA RL2_DEIRA]] One of the primary rRNA binding proteins. Required for association of the 30S and 50S subunits to form the 70S ribosome, for tRNA binding and peptide bond formation. It has been suggested to have peptidyltransferase activity; this is somewhat controversial. Makes several contacts with the 16S rRNA in the 70S ribosome (By similarity).[HAMAP-Rule:MF_01320_B] [[http://www.uniprot.org/uniprot/RL35_DEIRA RL35_DEIRA]] Binds the 23S rRNA.[HAMAP-Rule:MF_00514] [[http://www.uniprot.org/uniprot/RL22_DEIRA RL22_DEIRA]] This protein binds specifically to 23S rRNA; its binding is stimulated by other ribosomal proteins, e.g. L4, L17, and L20. It is important during the early stages of 50S assembly. It makes multiple contacts with different domains of the 23S rRNA in the assembled 50S subunit and ribosome (By similarity).[HAMAP-Rule:MF_01331_B]  The globular domain of the protein is located by the polypeptide exit tunnel on the outside of the subunit while an extended beta-hairpin forms part of the wall of the tunnel. Forms a pair of "tweezers" with L32 that hold together two different domains of the 23S rRNA. Interacts with the tunnel-blocking modified macrolide azithromycin. Upon binding of the macrolide troleadomycin to the ribosome, the tip of the beta-hairpin is displaced, which severely restricts the tunnel. This and experiments in E.coli have led to the suggestion that it is part of the gating mechanism involved in translation arrest in the absence of the protein export system.[HAMAP-Rule:MF_01331_B] [[http://www.uniprot.org/uniprot/RL4_DEIRA RL4_DEIRA]] One of the primary rRNA binding proteins, this protein initially binds near the 5'-end of the 23S rRNA. It is important during the early stages of 50S assembly (By similarity).[HAMAP-Rule:MF_01328_B]  Makes multiple contacts with different domains of the 23S rRNA in the assembled 50S subunit.[HAMAP-Rule:MF_01328_B]  This protein is located close to the polypeptide exit tunnel, and interacts with the modified macrolide azithromycin, which blocks the tunnel.[HAMAP-Rule:MF_01328_B] [[http://www.uniprot.org/uniprot/RL17_DEIRA RL17_DEIRA]] Binds to the 23S rRNA.[HAMAP-Rule:MF_01368] [[http://www.uniprot.org/uniprot/RL31_DEIRA RL31_DEIRA]] Binds the 23S rRNA and interacts with the tRNA in the E site.[HAMAP-Rule:MF_00501] [[http://www.uniprot.org/uniprot/RL36_DEIRA RL36_DEIRA]] Binds the 23S rRNA.[HAMAP-Rule:MF_00251]  
[https://www.uniprot.org/uniprot/RL33_DEIRA RL33_DEIRA] Binds the 23S rRNA and the E site tRNA.[HAMAP-Rule:MF_00294]
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/sm/1sm1_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/sm/1sm1_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1sm1 ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
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</StructureSection>
</StructureSection>
[[Category: Deinococcus radiodurans]]
[[Category: Deinococcus radiodurans]]
[[Category: Bartels, H]]
[[Category: Large Structures]]
[[Category: Fucini, P]]
[[Category: Streptomyces graminofaciens]]
[[Category: Harms, J M]]
[[Category: Bartels H]]
[[Category: Schluenzen, F]]
[[Category: Fucini P]]
[[Category: Yonath, A]]
[[Category: Harms JM]]
[[Category: 50s ribosomal subunit]]
[[Category: Schluenzen F]]
[[Category: Dalfopristin]]
[[Category: Yonath A]]
[[Category: Quinupristin]]
[[Category: Ribosom-antibiotic complex]]
[[Category: Ribosome]]
[[Category: Ribosome-antibiotic complex]]
[[Category: Streptogramin]]
[[Category: Synercid]]

Latest revision as of 11:49, 14 July 2024

COMPLEX OF THE LARGE RIBOSOMAL SUBUNIT FROM DEINOCOCCUS RADIODURANS WITH QUINUPRISTIN AND DALFOPRISTINCOMPLEX OF THE LARGE RIBOSOMAL SUBUNIT FROM DEINOCOCCUS RADIODURANS WITH QUINUPRISTIN AND DALFOPRISTIN

Structural highlights

1sm1 is a 10 chain structure with sequence from Deinococcus radiodurans and Streptomyces graminofaciens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.42Å
Ligands:, , , , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RL33_DEIRA Binds the 23S rRNA and the E site tRNA.[HAMAP-Rule:MF_00294]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

BACKGROUND: The bacterial ribosome is a primary target of several classes of antibiotics. Investigation of the structure of the ribosomal subunits in complex with different antibiotics can reveal the mode of inhibition of ribosomal protein synthesis. Analysis of the interactions between antibiotics and the ribosome permits investigation of the specific effect of modifications leading to antimicrobial resistances.Streptogramins are unique among the ribosome-targeting antibiotics because they consist of two components, streptogramins A and B, which act synergistically. Each compound alone exhibits a weak bacteriostatic activity, whereas the combination can act bactericidal. The streptogramins A display a prolonged activity that even persists after removal of the drug. However, the mode of activity of the streptogramins has not yet been fully elucidated, despite a plethora of biochemical and structural data. RESULTS: The investigation of the crystal structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with the clinically relevant streptogramins quinupristin and dalfopristin reveals their unique inhibitory mechanism. Quinupristin, a streptogramin B compound, binds in the ribosomal exit tunnel in a similar manner and position as the macrolides, suggesting a similar inhibitory mechanism, namely blockage of the ribosomal tunnel. Dalfopristin, the corresponding streptogramin A compound, binds close to quinupristin directly within the peptidyl transferase centre affecting both A- and P-site occupation by tRNA molecules. CONCLUSIONS: The crystal structure indicates that the synergistic effect derives from direct interaction between both compounds and shared contacts with a single nucleotide, A2062. Upon binding of the streptogramins, the peptidyl transferase centre undergoes a significant conformational transition, which leads to a stable, non-productive orientation of the universally conserved U2585. Mutations of this rRNA base are known to yield dominant lethal phenotypes. It seems, therefore, plausible to conclude that the conformational change within the peptidyl transferase centre is mainly responsible for the bactericidal activity of the streptogramins and the post-antibiotic inhibition of protein synthesis.

Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the streptogramins dalfopristin and quinupristin.,Harms JM, Schlunzen F, Fucini P, Bartels H, Yonath A BMC Biol. 2004 Apr 1;2:4. PMID:15059283[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Harms JM, Schlunzen F, Fucini P, Bartels H, Yonath A. Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the streptogramins dalfopristin and quinupristin. BMC Biol. 2004 Apr 1;2:4. PMID:15059283 doi:10.1186/1741-7007-2-4

1sm1, resolution 3.42Å

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