The Role of Sugar Residues in Molecular Recognition by Vancomycin
The sugar residues of the glycopeptide antibiotic vancomycin contribute to the cooperativity of ligand binding, thereby increasing ligand affinity and enhancing antimicrobial activity. To assess the structural basis for these effects, we determined a 0.98 Å X-ray crystal structure of the vancomycin...
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| Veröffentlicht in: | J. Med. Chem 2001-05, Vol.44 (11), p.1837-1840 |
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| container_title | J. Med. Chem |
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| creator | Kaplan, Jeffrey Korty, Brian D Axelsen, Paul H Loll, Patrick J |
| description | The sugar residues of the glycopeptide antibiotic vancomycin contribute to the cooperativity of ligand binding, thereby increasing ligand affinity and enhancing antimicrobial activity. To assess the structural basis for these effects, we determined a 0.98 Å X-ray crystal structure of the vancomycin aglycon and compared it to structures of several intact vancomycin:ligand complexes. The crystal structure reveals that the aglycon binds acetate anions and forms back-to-back dimeric complexes in a manner similar to that of intact vancomycin. However, the four independent copies of the aglycon in each asymmetric unit of the crystal exhibit a high degree of conformational heterogeneity. These results suggest that the sugar residues, in addition to enlarging and strengthening the dimer interface, provide steric constraints that limit the vancomycin molecule to a relatively small number of productive conformations. |
| doi_str_mv | 10.1021/jm0005306 |
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To assess the structural basis for these effects, we determined a 0.98 Å X-ray crystal structure of the vancomycin aglycon and compared it to structures of several intact vancomycin:ligand complexes. The crystal structure reveals that the aglycon binds acetate anions and forms back-to-back dimeric complexes in a manner similar to that of intact vancomycin. However, the four independent copies of the aglycon in each asymmetric unit of the crystal exhibit a high degree of conformational heterogeneity. These results suggest that the sugar residues, in addition to enlarging and strengthening the dimer interface, provide steric constraints that limit the vancomycin molecule to a relatively small number of productive conformations.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm0005306</identifier><identifier>PMID: 11356118</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Antibacterial agents ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; BASIC BIOLOGICAL SCIENCES ; Biological and medical sciences ; Carbohydrates - chemistry ; Crystallography, X-Ray ; Dimerization ; FUNGI ; Medical sciences ; Molecular Structure ; MOLECULES ; NATIONAL SYNCHROTRON LIGHT SOURCE ; PATTERN RECOGNITION ; Pharmacology. Drug treatments ; RESIDUES ; SACCHAROSE ; Terminology as Topic ; Vancomycin - chemistry</subject><ispartof>J. Med. Chem, 2001-05, Vol.44 (11), p.1837-1840</ispartof><rights>Copyright © 2001 American Chemical Society</rights><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a404t-f885cc18df97eea3f57a7d626afef2e0e4dfed0182b9449ccf0b3e8966ac2c513</citedby><cites>FETCH-LOGICAL-a404t-f885cc18df97eea3f57a7d626afef2e0e4dfed0182b9449ccf0b3e8966ac2c513</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm0005306$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm0005306$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1051573$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11356118$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/796337$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Kaplan, Jeffrey</creatorcontrib><creatorcontrib>Korty, Brian D</creatorcontrib><creatorcontrib>Axelsen, Paul H</creatorcontrib><creatorcontrib>Loll, Patrick J</creatorcontrib><creatorcontrib>Brookhaven National Lab., Upton, NY (US)</creatorcontrib><creatorcontrib>National Synchrotron Light Source (US)</creatorcontrib><title>The Role of Sugar Residues in Molecular Recognition by Vancomycin</title><title>J. Med. Chem</title><addtitle>J. Med. Chem</addtitle><description>The sugar residues of the glycopeptide antibiotic vancomycin contribute to the cooperativity of ligand binding, thereby increasing ligand affinity and enhancing antimicrobial activity. To assess the structural basis for these effects, we determined a 0.98 Å X-ray crystal structure of the vancomycin aglycon and compared it to structures of several intact vancomycin:ligand complexes. The crystal structure reveals that the aglycon binds acetate anions and forms back-to-back dimeric complexes in a manner similar to that of intact vancomycin. However, the four independent copies of the aglycon in each asymmetric unit of the crystal exhibit a high degree of conformational heterogeneity. These results suggest that the sugar residues, in addition to enlarging and strengthening the dimer interface, provide steric constraints that limit the vancomycin molecule to a relatively small number of productive conformations.</description><subject>Antibacterial agents</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Biological and medical sciences</subject><subject>Carbohydrates - chemistry</subject><subject>Crystallography, X-Ray</subject><subject>Dimerization</subject><subject>FUNGI</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>MOLECULES</subject><subject>NATIONAL SYNCHROTRON LIGHT SOURCE</subject><subject>PATTERN RECOGNITION</subject><subject>Pharmacology. Drug treatments</subject><subject>RESIDUES</subject><subject>SACCHAROSE</subject><subject>Terminology as Topic</subject><subject>Vancomycin - chemistry</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0M1u1DAUBWALUdFpYcELoCABEouAf2I7WValFKQCVWeApeW5uW49JHGxE6nz9niaUWHBypLvp2PfQ8hzRt8xytn7TU8plYKqR2TBJKdlVdPqMVlQynnJFReH5CilTUaCcfGEHDImpGKsXpCT1Q0WV6HDIrhiOV3bWFxh8u2EqfBD8SVPYOrubyFcD370YSjW2-KHHSD0W_DDU3LgbJfw2f48Jt8_nq1OP5UX384_n55clLai1Vi6upYArG5doxGtcFJb3SqurEPHkWLVOmwpq_m6qaoGwNG1wLpRygIHycQxeTnnhjR6k8CPCDcQhgFhNLpRQuhs3szmNobfeYXR9D4Bdp0dMEzJaForTqsdfDtDiCGliM7cRt_buDWMml2n5qHTbF_sQ6d1j-1fuS8xg1d7YBPYzsXcjU__JEomtcisnJlPI949jG38ZZQWWprV5dL8VOLD5delNrt3X8_eQjKbMMUh1_uf__0Bw7mXrw</recordid><startdate>20010524</startdate><enddate>20010524</enddate><creator>Kaplan, Jeffrey</creator><creator>Korty, Brian D</creator><creator>Axelsen, Paul H</creator><creator>Loll, Patrick J</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>OTOTI</scope></search><sort><creationdate>20010524</creationdate><title>The Role of Sugar Residues in Molecular Recognition by Vancomycin</title><author>Kaplan, Jeffrey ; Korty, Brian D ; Axelsen, Paul H ; Loll, Patrick J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a404t-f885cc18df97eea3f57a7d626afef2e0e4dfed0182b9449ccf0b3e8966ac2c513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Antibacterial agents</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Biological and medical sciences</topic><topic>Carbohydrates - chemistry</topic><topic>Crystallography, X-Ray</topic><topic>Dimerization</topic><topic>FUNGI</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>MOLECULES</topic><topic>NATIONAL SYNCHROTRON LIGHT SOURCE</topic><topic>PATTERN RECOGNITION</topic><topic>Pharmacology. Drug treatments</topic><topic>RESIDUES</topic><topic>SACCHAROSE</topic><topic>Terminology as Topic</topic><topic>Vancomycin - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kaplan, Jeffrey</creatorcontrib><creatorcontrib>Korty, Brian D</creatorcontrib><creatorcontrib>Axelsen, Paul H</creatorcontrib><creatorcontrib>Loll, Patrick J</creatorcontrib><creatorcontrib>Brookhaven National Lab., Upton, NY (US)</creatorcontrib><creatorcontrib>National Synchrotron Light Source (US)</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV</collection><jtitle>J. Med. Chem</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kaplan, Jeffrey</au><au>Korty, Brian D</au><au>Axelsen, Paul H</au><au>Loll, Patrick J</au><aucorp>Brookhaven National Lab., Upton, NY (US)</aucorp><aucorp>National Synchrotron Light Source (US)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Role of Sugar Residues in Molecular Recognition by Vancomycin</atitle><jtitle>J. Med. Chem</jtitle><addtitle>J. Med. Chem</addtitle><date>2001-05-24</date><risdate>2001</risdate><volume>44</volume><issue>11</issue><spage>1837</spage><epage>1840</epage><pages>1837-1840</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The sugar residues of the glycopeptide antibiotic vancomycin contribute to the cooperativity of ligand binding, thereby increasing ligand affinity and enhancing antimicrobial activity. To assess the structural basis for these effects, we determined a 0.98 Å X-ray crystal structure of the vancomycin aglycon and compared it to structures of several intact vancomycin:ligand complexes. The crystal structure reveals that the aglycon binds acetate anions and forms back-to-back dimeric complexes in a manner similar to that of intact vancomycin. However, the four independent copies of the aglycon in each asymmetric unit of the crystal exhibit a high degree of conformational heterogeneity. These results suggest that the sugar residues, in addition to enlarging and strengthening the dimer interface, provide steric constraints that limit the vancomycin molecule to a relatively small number of productive conformations.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>11356118</pmid><doi>10.1021/jm0005306</doi><tpages>4</tpages></addata></record> |
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| subjects | Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents BASIC BIOLOGICAL SCIENCES Biological and medical sciences Carbohydrates - chemistry Crystallography, X-Ray Dimerization FUNGI Medical sciences Molecular Structure MOLECULES NATIONAL SYNCHROTRON LIGHT SOURCE PATTERN RECOGNITION Pharmacology. Drug treatments RESIDUES SACCHAROSE Terminology as Topic Vancomycin - chemistry |
| title | The Role of Sugar Residues in Molecular Recognition by Vancomycin |
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