Induced-fit tightens pleuromutilins binding to ribosomes and remote interactions enable their selectivity
New insights into functional flexibility at the peptidyl transferase center (PTC) and its vicinity were obtained by analysis of pleuromutilins binding modes to the ribosome. The crystal structures of Deinococcus radiodurans large ribosomal subunit complexed with each of three pleuromutilin derivativ...
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| Veröffentlicht in: | Proc. Natl. Acad. Sci. USA 2007-03, Vol.104 (11), p.4291-4296 |
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| creator | Davidovich, Chen Bashan, Anat Auerbach-Nevo, Tamar Yaggie, Rachel D Gontarek, Richard R Yonath, Ada |
| description | New insights into functional flexibility at the peptidyl transferase center (PTC) and its vicinity were obtained by analysis of pleuromutilins binding modes to the ribosome. The crystal structures of Deinococcus radiodurans large ribosomal subunit complexed with each of three pleuromutilin derivatives: retapamulin (SB-275833), SB-280080, and SB-571519, show that all bind to the PTC with their core oriented similarly at the A-site and their C14 extensions pointing toward the P-site. Except for an H-bond network with a single nucleotide, G2061, which involves the essential keto group of all three compounds, only minor hydrophobic contacts are formed between the pleuromutilin C14 extensions and any ribosomal component, consistent with the PTC tolerance to amino acid diversity. Efficient drug binding mode is attained by a mechanism based on induced-fit motions exploiting the ribosomal intrinsic functional flexibility and resulting in conformational rearrangements that seal the pleuromutilin-binding pocket and tightens it up. Comparative studies identified a network of remote interactions around the PTC, indicating that pleuromutilins selectivity is acquired by nonconserved nucleotides residing in the PTC vicinity, in a fashion resembling allosterism. Likewise, pleuromutilin resistant mechanisms involve nucleotides residing in the environs of the binding pocket, consistent with their slow resistance-development rates. |
| doi_str_mv | 10.1073/pnas.0700041104 |
| format | Article |
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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>New insights into functional flexibility at the peptidyl transferase center (PTC) and its vicinity were obtained by analysis of pleuromutilins binding modes to the ribosome. The crystal structures of Deinococcus radiodurans large ribosomal subunit complexed with each of three pleuromutilin derivatives: retapamulin (SB-275833), SB-280080, and SB-571519, show that all bind to the PTC with their core oriented similarly at the A-site and their C14 extensions pointing toward the P-site. Except for an H-bond network with a single nucleotide, G2061, which involves the essential keto group of all three compounds, only minor hydrophobic contacts are formed between the pleuromutilin C14 extensions and any ribosomal component, consistent with the PTC tolerance to amino acid diversity. Efficient drug binding mode is attained by a mechanism based on induced-fit motions exploiting the ribosomal intrinsic functional flexibility and resulting in conformational rearrangements that seal the pleuromutilin-binding pocket and tightens it up. Comparative studies identified a network of remote interactions around the PTC, indicating that pleuromutilins selectivity is acquired by nonconserved nucleotides residing in the PTC vicinity, in a fashion resembling allosterism. Likewise, pleuromutilin resistant mechanisms involve nucleotides residing in the environs of the binding pocket, consistent with their slow resistance-development rates.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0700041104</identifier><identifier>PMID: 17360517</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Allosteric Site ; Amino Acid Sequence ; Anti-Bacterial Agents - chemistry ; Antibiotics ; Bacteria ; Binding sites ; Biochemistry ; Biological Sciences ; Bridged Bicyclo Compounds, Heterocyclic - chemistry ; Chromosomes ; Crystal structure ; Crystallography, X-Ray ; Deinococcus - metabolism ; Deinococcus radiodurans ; Diterpenes - chemistry ; Escherichia coli - metabolism ; Flexibility ; Hydroxyls ; Kinetics ; Models, Chemical ; Models, Molecular ; Molecular Sequence Data ; Nucleotides ; Pathogens ; Phosphates ; Pleuromutilins ; Polycyclic Compounds ; Protein Binding ; Protein Structure, Tertiary ; Radiocarbon ; Ribosomes ; Ribosomes - chemistry</subject><ispartof>Proc. 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USA, 2007-03, Vol.104 (11), p.4291-4296</ispartof><rights>Copyright 2007 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Mar 13, 2007</rights><rights>2007 by The National Academy of Sciences of the USA 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c579t-da27323e8eabf9ef96005519f76d66374575b97a37674c8f6916b5279f2ebe603</citedby><cites>FETCH-LOGICAL-c579t-da27323e8eabf9ef96005519f76d66374575b97a37674c8f6916b5279f2ebe603</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/104/11.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25426826$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25426826$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17360517$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1169983$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Davidovich, Chen</creatorcontrib><creatorcontrib>Bashan, Anat</creatorcontrib><creatorcontrib>Auerbach-Nevo, Tamar</creatorcontrib><creatorcontrib>Yaggie, Rachel D</creatorcontrib><creatorcontrib>Gontarek, Richard R</creatorcontrib><creatorcontrib>Yonath, Ada</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Induced-fit tightens pleuromutilins binding to ribosomes and remote interactions enable their selectivity</title><title>Proc. Natl. Acad. Sci. USA</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>New insights into functional flexibility at the peptidyl transferase center (PTC) and its vicinity were obtained by analysis of pleuromutilins binding modes to the ribosome. The crystal structures of Deinococcus radiodurans large ribosomal subunit complexed with each of three pleuromutilin derivatives: retapamulin (SB-275833), SB-280080, and SB-571519, show that all bind to the PTC with their core oriented similarly at the A-site and their C14 extensions pointing toward the P-site. Except for an H-bond network with a single nucleotide, G2061, which involves the essential keto group of all three compounds, only minor hydrophobic contacts are formed between the pleuromutilin C14 extensions and any ribosomal component, consistent with the PTC tolerance to amino acid diversity. Efficient drug binding mode is attained by a mechanism based on induced-fit motions exploiting the ribosomal intrinsic functional flexibility and resulting in conformational rearrangements that seal the pleuromutilin-binding pocket and tightens it up. Comparative studies identified a network of remote interactions around the PTC, indicating that pleuromutilins selectivity is acquired by nonconserved nucleotides residing in the PTC vicinity, in a fashion resembling allosterism. 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Natl. Acad. Sci. USA</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Davidovich, Chen</au><au>Bashan, Anat</au><au>Auerbach-Nevo, Tamar</au><au>Yaggie, Rachel D</au><au>Gontarek, Richard R</au><au>Yonath, Ada</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Induced-fit tightens pleuromutilins binding to ribosomes and remote interactions enable their selectivity</atitle><jtitle>Proc. Natl. Acad. Sci. USA</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2007-03-13</date><risdate>2007</risdate><volume>104</volume><issue>11</issue><spage>4291</spage><epage>4296</epage><pages>4291-4296</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>New insights into functional flexibility at the peptidyl transferase center (PTC) and its vicinity were obtained by analysis of pleuromutilins binding modes to the ribosome. The crystal structures of Deinococcus radiodurans large ribosomal subunit complexed with each of three pleuromutilin derivatives: retapamulin (SB-275833), SB-280080, and SB-571519, show that all bind to the PTC with their core oriented similarly at the A-site and their C14 extensions pointing toward the P-site. Except for an H-bond network with a single nucleotide, G2061, which involves the essential keto group of all three compounds, only minor hydrophobic contacts are formed between the pleuromutilin C14 extensions and any ribosomal component, consistent with the PTC tolerance to amino acid diversity. Efficient drug binding mode is attained by a mechanism based on induced-fit motions exploiting the ribosomal intrinsic functional flexibility and resulting in conformational rearrangements that seal the pleuromutilin-binding pocket and tightens it up. Comparative studies identified a network of remote interactions around the PTC, indicating that pleuromutilins selectivity is acquired by nonconserved nucleotides residing in the PTC vicinity, in a fashion resembling allosterism. Likewise, pleuromutilin resistant mechanisms involve nucleotides residing in the environs of the binding pocket, consistent with their slow resistance-development rates.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>17360517</pmid><doi>10.1073/pnas.0700041104</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; JSTOR Archive Collection A-Z Listing; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Allosteric Site Amino Acid Sequence Anti-Bacterial Agents - chemistry Antibiotics Bacteria Binding sites Biochemistry Biological Sciences Bridged Bicyclo Compounds, Heterocyclic - chemistry Chromosomes Crystal structure Crystallography, X-Ray Deinococcus - metabolism Deinococcus radiodurans Diterpenes - chemistry Escherichia coli - metabolism Flexibility Hydroxyls Kinetics Models, Chemical Models, Molecular Molecular Sequence Data Nucleotides Pathogens Phosphates Pleuromutilins Polycyclic Compounds Protein Binding Protein Structure, Tertiary Radiocarbon Ribosomes Ribosomes - chemistry |
| title | Induced-fit tightens pleuromutilins binding to ribosomes and remote interactions enable their selectivity |
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