A Comparison of the Anti-rhinoviral Drug Binding Pocket in HRV14 and HRV1A
The three-dimensional structures of two human rhinovirus serotypes (HRV14 and HRV1A) are compared when complexed with various antiviral agents. Although these agents all bind into the same hydrophobic pocket, the exact viral-drug interactions differ. In the absence of drugs, the pocket is occupied b...
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| Veröffentlicht in: | Journal of molecular biology 1993-03, Vol.230 (1), p.206-226 |
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| creator | Kim, Kyung H. Willingmann, Peter Gong, Zu Xun Kremer, Marcia J. Chapman, Michael S. Minor, Iwona Oliveira, Marcos A. Rossmann, Michael G. Andries, Koen Diana, Guy D. Dutko, Frank J. McKinlay, Mark A. Pevear, Daniel C. |
| description | The three-dimensional structures of two human rhinovirus serotypes (HRV14 and HRV1A) are compared when complexed with various antiviral agents. Although these agents all bind into the same hydrophobic pocket, the exact viral-drug interactions differ. In the absence of drugs, the pocket is occupied by a fatty acid in HRV1A, but is empty in HRV14 except for two water molecules. The conformation of each drug is dependent upon the shape of the hydrophobic pocket. In HRV14 the major residues determining the shape of the binding site are Y1128, P1174 and M1224, corresponding to I1125, M1169 and I1220 in HRV1A. When there is no cofactor or a drug in the pocket, the entrance to the pocket is open. However, the entrance is closed when the pocket is occupied by a cofactor or a drug. There are relatively small conformational changes when the agents displace the natural cofactor in HRV1A. In contrast, there are much larger conformational changes on binding a drug in HRV14. These differences cause an inhibition of viral attachment in HRV14 but not in HRV1A. Binding of the drugs results in three additional interprotomer hydrogen bonds in HRV14 and one in HRV1A. These hydrogen bonds and a potential loss of flexibility upon efficient packing of the pocket may contribute to the inhibition of uncoating in both serotypes. |
| doi_str_mv | 10.1006/jmbi.1993.1137 |
| format | Article |
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Although these agents all bind into the same hydrophobic pocket, the exact viral-drug interactions differ. In the absence of drugs, the pocket is occupied by a fatty acid in HRV1A, but is empty in HRV14 except for two water molecules. The conformation of each drug is dependent upon the shape of the hydrophobic pocket. In HRV14 the major residues determining the shape of the binding site are Y1128, P1174 and M1224, corresponding to I1125, M1169 and I1220 in HRV1A. When there is no cofactor or a drug in the pocket, the entrance to the pocket is open. However, the entrance is closed when the pocket is occupied by a cofactor or a drug. There are relatively small conformational changes when the agents displace the natural cofactor in HRV1A. In contrast, there are much larger conformational changes on binding a drug in HRV14. These differences cause an inhibition of viral attachment in HRV14 but not in HRV1A. Binding of the drugs results in three additional interprotomer hydrogen bonds in HRV14 and one in HRV1A. These hydrogen bonds and a potential loss of flexibility upon efficient packing of the pocket may contribute to the inhibition of uncoating in both serotypes.</description><identifier>ISSN: 0022-2836</identifier><identifier>EISSN: 1089-8638</identifier><identifier>DOI: 10.1006/jmbi.1993.1137</identifier><identifier>PMID: 8383771</identifier><identifier>CODEN: JMOBAK</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Amino Acid Sequence ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; antiviral ; Antiviral agents ; Antiviral Agents - chemistry ; Binding Sites ; Biological and medical sciences ; Capsid - ultrastructure ; Conserved Sequence ; Drug Design ; drugs ; HRV14 ; HRV1A ; Isoxazoles - chemistry ; Medical sciences ; Models, Molecular ; Molecular Sequence Data ; Pharmacology. Drug treatments ; Pyridazines - chemistry ; rhinovirus ; Rhinovirus - classification ; Rhinovirus - drug effects ; Rhinovirus - ultrastructure ; Sequence Alignment ; Serotyping ; Structure-Activity Relationship</subject><ispartof>Journal of molecular biology, 1993-03, Vol.230 (1), p.206-226</ispartof><rights>1993 Academic Press</rights><rights>1993 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c368t-fb07287cf63e39b88855b667c74d98aa0e6503bd257c61622c9c8958b574d3ad3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1006/jmbi.1993.1137$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4639552$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8383771$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Kyung H.</creatorcontrib><creatorcontrib>Willingmann, Peter</creatorcontrib><creatorcontrib>Gong, Zu Xun</creatorcontrib><creatorcontrib>Kremer, Marcia J.</creatorcontrib><creatorcontrib>Chapman, Michael S.</creatorcontrib><creatorcontrib>Minor, Iwona</creatorcontrib><creatorcontrib>Oliveira, Marcos A.</creatorcontrib><creatorcontrib>Rossmann, Michael G.</creatorcontrib><creatorcontrib>Andries, Koen</creatorcontrib><creatorcontrib>Diana, Guy D.</creatorcontrib><creatorcontrib>Dutko, Frank J.</creatorcontrib><creatorcontrib>McKinlay, Mark A.</creatorcontrib><creatorcontrib>Pevear, Daniel C.</creatorcontrib><title>A Comparison of the Anti-rhinoviral Drug Binding Pocket in HRV14 and HRV1A</title><title>Journal of molecular biology</title><addtitle>J Mol Biol</addtitle><description>The three-dimensional structures of two human rhinovirus serotypes (HRV14 and HRV1A) are compared when complexed with various antiviral agents. Although these agents all bind into the same hydrophobic pocket, the exact viral-drug interactions differ. In the absence of drugs, the pocket is occupied by a fatty acid in HRV1A, but is empty in HRV14 except for two water molecules. The conformation of each drug is dependent upon the shape of the hydrophobic pocket. In HRV14 the major residues determining the shape of the binding site are Y1128, P1174 and M1224, corresponding to I1125, M1169 and I1220 in HRV1A. When there is no cofactor or a drug in the pocket, the entrance to the pocket is open. However, the entrance is closed when the pocket is occupied by a cofactor or a drug. There are relatively small conformational changes when the agents displace the natural cofactor in HRV1A. In contrast, there are much larger conformational changes on binding a drug in HRV14. These differences cause an inhibition of viral attachment in HRV14 but not in HRV1A. Binding of the drugs results in three additional interprotomer hydrogen bonds in HRV14 and one in HRV1A. These hydrogen bonds and a potential loss of flexibility upon efficient packing of the pocket may contribute to the inhibition of uncoating in both serotypes.</description><subject>Amino Acid Sequence</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>antiviral</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemistry</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Capsid - ultrastructure</subject><subject>Conserved Sequence</subject><subject>Drug Design</subject><subject>drugs</subject><subject>HRV14</subject><subject>HRV1A</subject><subject>Isoxazoles - chemistry</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyridazines - chemistry</subject><subject>rhinovirus</subject><subject>Rhinovirus - classification</subject><subject>Rhinovirus - drug effects</subject><subject>Rhinovirus - ultrastructure</subject><subject>Sequence Alignment</subject><subject>Serotyping</subject><subject>Structure-Activity Relationship</subject><issn>0022-2836</issn><issn>1089-8638</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kEtLAzEURoMotT627oQsxN3UPJrHLGt9VCkoom5DJpNpU2eSmkwL_nuntnTn6l74zv24HAAuMBpghPjNoincAOc5HWBMxQHoYyTzTHIqD0EfIUIyIik_BicpLRBCjA5lD_QklVQI3AfPIzgOzVJHl4KHoYLt3MKRb10W586HtYu6hndxNYO3zpfOz-BrMF-2hc7DydsnHkLty79tdAaOKl0ne76bp-Dj4f59PMmmL49P49E0M5TLNqsKJIgUpuLU0ryQUjJWcC6MGJa51BpZzhAtSsKE4ZgTYnIjcyYL1gFUl_QUXG97lzF8r2xqVeOSsXWtvQ2rpATjmFCKOnCwBU0MKUVbqWV0jY4_CiO1kac28tRGntrI6w4ud82rorHlHt_Z6vKrXa6T0XUVtTcu7bEhpzljpMPkFrOdhbWzUSXjrDe2dNGaVpXB_ffBL91lh54</recordid><startdate>19930305</startdate><enddate>19930305</enddate><creator>Kim, Kyung H.</creator><creator>Willingmann, Peter</creator><creator>Gong, Zu Xun</creator><creator>Kremer, Marcia J.</creator><creator>Chapman, Michael S.</creator><creator>Minor, Iwona</creator><creator>Oliveira, Marcos A.</creator><creator>Rossmann, Michael G.</creator><creator>Andries, Koen</creator><creator>Diana, Guy D.</creator><creator>Dutko, Frank J.</creator><creator>McKinlay, Mark A.</creator><creator>Pevear, Daniel C.</creator><general>Elsevier Ltd</general><general>Elsevier</general><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></search><sort><creationdate>19930305</creationdate><title>A Comparison of the Anti-rhinoviral Drug Binding Pocket in HRV14 and HRV1A</title><author>Kim, Kyung H. ; Willingmann, Peter ; Gong, Zu Xun ; Kremer, Marcia J. ; Chapman, Michael S. ; Minor, Iwona ; Oliveira, Marcos A. ; Rossmann, Michael G. ; Andries, Koen ; Diana, Guy D. ; Dutko, Frank J. ; McKinlay, Mark A. ; Pevear, Daniel C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c368t-fb07287cf63e39b88855b667c74d98aa0e6503bd257c61622c9c8958b574d3ad3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>Amino Acid Sequence</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>antiviral</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - chemistry</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Capsid - ultrastructure</topic><topic>Conserved Sequence</topic><topic>Drug Design</topic><topic>drugs</topic><topic>HRV14</topic><topic>HRV1A</topic><topic>Isoxazoles - chemistry</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyridazines - chemistry</topic><topic>rhinovirus</topic><topic>Rhinovirus - classification</topic><topic>Rhinovirus - drug effects</topic><topic>Rhinovirus - ultrastructure</topic><topic>Sequence Alignment</topic><topic>Serotyping</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Kyung H.</creatorcontrib><creatorcontrib>Willingmann, Peter</creatorcontrib><creatorcontrib>Gong, Zu Xun</creatorcontrib><creatorcontrib>Kremer, Marcia J.</creatorcontrib><creatorcontrib>Chapman, Michael S.</creatorcontrib><creatorcontrib>Minor, Iwona</creatorcontrib><creatorcontrib>Oliveira, Marcos A.</creatorcontrib><creatorcontrib>Rossmann, Michael G.</creatorcontrib><creatorcontrib>Andries, Koen</creatorcontrib><creatorcontrib>Diana, Guy D.</creatorcontrib><creatorcontrib>Dutko, Frank J.</creatorcontrib><creatorcontrib>McKinlay, Mark A.</creatorcontrib><creatorcontrib>Pevear, Daniel C.</creatorcontrib><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><jtitle>Journal of molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Kyung H.</au><au>Willingmann, Peter</au><au>Gong, Zu Xun</au><au>Kremer, Marcia J.</au><au>Chapman, Michael S.</au><au>Minor, Iwona</au><au>Oliveira, Marcos A.</au><au>Rossmann, Michael G.</au><au>Andries, Koen</au><au>Diana, Guy D.</au><au>Dutko, Frank J.</au><au>McKinlay, Mark A.</au><au>Pevear, Daniel C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Comparison of the Anti-rhinoviral Drug Binding Pocket in HRV14 and HRV1A</atitle><jtitle>Journal of molecular biology</jtitle><addtitle>J Mol Biol</addtitle><date>1993-03-05</date><risdate>1993</risdate><volume>230</volume><issue>1</issue><spage>206</spage><epage>226</epage><pages>206-226</pages><issn>0022-2836</issn><eissn>1089-8638</eissn><coden>JMOBAK</coden><abstract>The three-dimensional structures of two human rhinovirus serotypes (HRV14 and HRV1A) are compared when complexed with various antiviral agents. Although these agents all bind into the same hydrophobic pocket, the exact viral-drug interactions differ. In the absence of drugs, the pocket is occupied by a fatty acid in HRV1A, but is empty in HRV14 except for two water molecules. The conformation of each drug is dependent upon the shape of the hydrophobic pocket. In HRV14 the major residues determining the shape of the binding site are Y1128, P1174 and M1224, corresponding to I1125, M1169 and I1220 in HRV1A. When there is no cofactor or a drug in the pocket, the entrance to the pocket is open. However, the entrance is closed when the pocket is occupied by a cofactor or a drug. There are relatively small conformational changes when the agents displace the natural cofactor in HRV1A. In contrast, there are much larger conformational changes on binding a drug in HRV14. These differences cause an inhibition of viral attachment in HRV14 but not in HRV1A. Binding of the drugs results in three additional interprotomer hydrogen bonds in HRV14 and one in HRV1A. These hydrogen bonds and a potential loss of flexibility upon efficient packing of the pocket may contribute to the inhibition of uncoating in both serotypes.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>8383771</pmid><doi>10.1006/jmbi.1993.1137</doi><tpages>21</tpages></addata></record> |
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| ispartof | Journal of molecular biology, 1993-03, Vol.230 (1), p.206-226 |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Amino Acid Sequence Antibiotics. Antiinfectious agents. Antiparasitic agents antiviral Antiviral agents Antiviral Agents - chemistry Binding Sites Biological and medical sciences Capsid - ultrastructure Conserved Sequence Drug Design drugs HRV14 HRV1A Isoxazoles - chemistry Medical sciences Models, Molecular Molecular Sequence Data Pharmacology. Drug treatments Pyridazines - chemistry rhinovirus Rhinovirus - classification Rhinovirus - drug effects Rhinovirus - ultrastructure Sequence Alignment Serotyping Structure-Activity Relationship |
| title | A Comparison of the Anti-rhinoviral Drug Binding Pocket in HRV14 and HRV1A |
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