Structure-based Active Site Profiles for Genome Analysis and Functional Family Subclassification
In previous work, structure-based functional site descriptors, fuzzy functional forms (FFFs), were developed to recognize structurally conserved active sites in proteins. These descriptors identify members of protein families according to active-site structural similarity, rather than overall sequen...
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Veröffentlicht in: | Journal of molecular biology 2003-11, Vol.334 (3), p.387-401 |
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description | In previous work, structure-based functional site descriptors, fuzzy functional forms (FFFs), were developed to recognize structurally conserved active sites in proteins. These descriptors identify members of protein families according to active-site structural similarity, rather than overall sequence or structure similarity. FFFs are defined by a minimal number of highly conserved residues and their three-dimensional arrangement. This approach is advantageous for function assignment across broad families, but is limited when applied to detailed subclassification within these families. In the work described here, we developed a method of three-dimensional, or structure-based, active-site profiling that utilizes FFFs to identify residues located in the spatial environment around the active site. Three-dimensional active-site profiling reveals similarities and differences among active sites across protein families. Using this approach, active-site profiles were constructed from known structures for 193 functional families, and these profiles were verified as distinct and characteristic. To achieve this result, a scoring function was developed that discriminates between true functional sites and those that are geometrically most similar, but do not perform the same function. In a large-scale retrospective analysis of human genome sequences, this profile score was shown to identify specific functional families correctly. The method is effective at recognizing the likely subtype of structurally uncharacterized members of the diverse family of protein kinases, categorizing sequences correctly that were misclassified by global sequence alignment methods. Subfamily information provided by this three-dimensional active-site profiling method yields key information for specific and selective inhibitor design for use in the pharmaceutical industry. |
doi_str_mv | 10.1016/j.jmb.2003.09.062 |
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These descriptors identify members of protein families according to active-site structural similarity, rather than overall sequence or structure similarity. FFFs are defined by a minimal number of highly conserved residues and their three-dimensional arrangement. This approach is advantageous for function assignment across broad families, but is limited when applied to detailed subclassification within these families. In the work described here, we developed a method of three-dimensional, or structure-based, active-site profiling that utilizes FFFs to identify residues located in the spatial environment around the active site. Three-dimensional active-site profiling reveals similarities and differences among active sites across protein families. Using this approach, active-site profiles were constructed from known structures for 193 functional families, and these profiles were verified as distinct and characteristic. To achieve this result, a scoring function was developed that discriminates between true functional sites and those that are geometrically most similar, but do not perform the same function. In a large-scale retrospective analysis of human genome sequences, this profile score was shown to identify specific functional families correctly. The method is effective at recognizing the likely subtype of structurally uncharacterized members of the diverse family of protein kinases, categorizing sequences correctly that were misclassified by global sequence alignment methods. Subfamily information provided by this three-dimensional active-site profiling method yields key information for specific and selective inhibitor design for use in the pharmaceutical industry.</description><identifier>ISSN: 0022-2836</identifier><identifier>EISSN: 1089-8638</identifier><identifier>DOI: 10.1016/j.jmb.2003.09.062</identifier><identifier>PMID: 14623182</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>active site ; active-site profile ; Algorithms ; Amino Acid Sequence ; Binding Sites ; fuzzy functional form ; Genome, Human ; Humans ; Models, Molecular ; Molecular Sequence Data ; Protein Folding ; Protein Structure, Tertiary ; Proteins - chemistry ; Proteins - classification ; Proteins - physiology ; Sequence Alignment ; Sequence Homology, Amino Acid ; structure motifs ; Structure-Activity Relationship ; structure-based function annotation</subject><ispartof>Journal of molecular biology, 2003-11, Vol.334 (3), p.387-401</ispartof><rights>2003 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c380t-d44293b7b6f6ee26456b1c6aa4c6699ef37b003dff5c2a413af02c81968718a63</citedby><cites>FETCH-LOGICAL-c380t-d44293b7b6f6ee26456b1c6aa4c6699ef37b003dff5c2a413af02c81968718a63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0022283603012270$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27902,27903,65308</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14623182$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cammer, Stephen A.</creatorcontrib><creatorcontrib>Hoffman, Brian T.</creatorcontrib><creatorcontrib>Speir, Jeffrey A.</creatorcontrib><creatorcontrib>Canady, Mary A.</creatorcontrib><creatorcontrib>Nelson, Melanie R.</creatorcontrib><creatorcontrib>Knutson, Stacy</creatorcontrib><creatorcontrib>Gallina, Marijo</creatorcontrib><creatorcontrib>Baxter, Susan M.</creatorcontrib><creatorcontrib>Fetrow, Jacquelyn S.</creatorcontrib><title>Structure-based Active Site Profiles for Genome Analysis and Functional Family Subclassification</title><title>Journal of molecular biology</title><addtitle>J Mol Biol</addtitle><description>In previous work, structure-based functional site descriptors, fuzzy functional forms (FFFs), were developed to recognize structurally conserved active sites in proteins. These descriptors identify members of protein families according to active-site structural similarity, rather than overall sequence or structure similarity. FFFs are defined by a minimal number of highly conserved residues and their three-dimensional arrangement. This approach is advantageous for function assignment across broad families, but is limited when applied to detailed subclassification within these families. In the work described here, we developed a method of three-dimensional, or structure-based, active-site profiling that utilizes FFFs to identify residues located in the spatial environment around the active site. Three-dimensional active-site profiling reveals similarities and differences among active sites across protein families. Using this approach, active-site profiles were constructed from known structures for 193 functional families, and these profiles were verified as distinct and characteristic. To achieve this result, a scoring function was developed that discriminates between true functional sites and those that are geometrically most similar, but do not perform the same function. In a large-scale retrospective analysis of human genome sequences, this profile score was shown to identify specific functional families correctly. The method is effective at recognizing the likely subtype of structurally uncharacterized members of the diverse family of protein kinases, categorizing sequences correctly that were misclassified by global sequence alignment methods. Subfamily information provided by this three-dimensional active-site profiling method yields key information for specific and selective inhibitor design for use in the pharmaceutical industry.</description><subject>active site</subject><subject>active-site profile</subject><subject>Algorithms</subject><subject>Amino Acid Sequence</subject><subject>Binding Sites</subject><subject>fuzzy functional form</subject><subject>Genome, Human</subject><subject>Humans</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Protein Folding</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins - chemistry</subject><subject>Proteins - classification</subject><subject>Proteins - physiology</subject><subject>Sequence Alignment</subject><subject>Sequence Homology, Amino Acid</subject><subject>structure motifs</subject><subject>Structure-Activity Relationship</subject><subject>structure-based function annotation</subject><issn>0022-2836</issn><issn>1089-8638</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1LAzEQhoMotlZ_gBfJyduu-dhNs3gqYqtQUKieYzY7gSz7UZPdQv-9KS1409PAzPO-MA9Ct5SklFDxUKd1W6aMEJ6SIiWCnaEpJbJIpODyHE0JYSxhkosJugqhJoTkPJOXaEIzwTiVbIq-NoMfzTB6SEodoMILM7gd4I0bAL_73roGAra9xyvo-hbwotPNPriAdVfh5dhFvI8rvNSta_Z4M5am0SE464w-nK7RhdVNgJvTnKHP5fPH00uyflu9Pi3WieGSDEmVZazg5bwUVgAwkeWipEZonRkhigIsn5fxz8ra3DCdUa4tYUbSQsg5lVrwGbo_9m59_z1CGFTrgoGm0R30Y1BzymXE839BRjNOGaMRpEfQ-D4ED1ZtvWu13ytK1MG_qlX0rw7-FSlU9B8zd6fysWyh-k2chEfg8QhAdLFz4FUwDjoDlfNgBlX17o_6H8HHlhQ</recordid><startdate>20031128</startdate><enddate>20031128</enddate><creator>Cammer, Stephen A.</creator><creator>Hoffman, Brian T.</creator><creator>Speir, Jeffrey A.</creator><creator>Canady, Mary A.</creator><creator>Nelson, Melanie R.</creator><creator>Knutson, Stacy</creator><creator>Gallina, Marijo</creator><creator>Baxter, Susan M.</creator><creator>Fetrow, Jacquelyn S.</creator><general>Elsevier Ltd</general><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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20031128</creationdate><title>Structure-based Active Site Profiles for Genome Analysis and Functional Family Subclassification</title><author>Cammer, Stephen A. ; Hoffman, Brian T. ; Speir, Jeffrey A. ; Canady, Mary A. ; Nelson, Melanie R. ; Knutson, Stacy ; Gallina, Marijo ; Baxter, Susan M. ; Fetrow, Jacquelyn S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c380t-d44293b7b6f6ee26456b1c6aa4c6699ef37b003dff5c2a413af02c81968718a63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>active site</topic><topic>active-site profile</topic><topic>Algorithms</topic><topic>Amino Acid Sequence</topic><topic>Binding Sites</topic><topic>fuzzy functional form</topic><topic>Genome, Human</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Protein Folding</topic><topic>Protein Structure, Tertiary</topic><topic>Proteins - chemistry</topic><topic>Proteins - classification</topic><topic>Proteins - physiology</topic><topic>Sequence Alignment</topic><topic>Sequence Homology, Amino Acid</topic><topic>structure motifs</topic><topic>Structure-Activity Relationship</topic><topic>structure-based function annotation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cammer, Stephen A.</creatorcontrib><creatorcontrib>Hoffman, Brian T.</creatorcontrib><creatorcontrib>Speir, Jeffrey A.</creatorcontrib><creatorcontrib>Canady, Mary A.</creatorcontrib><creatorcontrib>Nelson, Melanie R.</creatorcontrib><creatorcontrib>Knutson, Stacy</creatorcontrib><creatorcontrib>Gallina, Marijo</creatorcontrib><creatorcontrib>Baxter, Susan M.</creatorcontrib><creatorcontrib>Fetrow, Jacquelyn S.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cammer, Stephen A.</au><au>Hoffman, Brian T.</au><au>Speir, Jeffrey A.</au><au>Canady, Mary A.</au><au>Nelson, Melanie R.</au><au>Knutson, Stacy</au><au>Gallina, Marijo</au><au>Baxter, Susan M.</au><au>Fetrow, Jacquelyn S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-based Active Site Profiles for Genome Analysis and Functional Family Subclassification</atitle><jtitle>Journal of molecular biology</jtitle><addtitle>J Mol Biol</addtitle><date>2003-11-28</date><risdate>2003</risdate><volume>334</volume><issue>3</issue><spage>387</spage><epage>401</epage><pages>387-401</pages><issn>0022-2836</issn><eissn>1089-8638</eissn><abstract>In previous work, structure-based functional site descriptors, fuzzy functional forms (FFFs), were developed to recognize structurally conserved active sites in proteins. These descriptors identify members of protein families according to active-site structural similarity, rather than overall sequence or structure similarity. FFFs are defined by a minimal number of highly conserved residues and their three-dimensional arrangement. This approach is advantageous for function assignment across broad families, but is limited when applied to detailed subclassification within these families. In the work described here, we developed a method of three-dimensional, or structure-based, active-site profiling that utilizes FFFs to identify residues located in the spatial environment around the active site. Three-dimensional active-site profiling reveals similarities and differences among active sites across protein families. Using this approach, active-site profiles were constructed from known structures for 193 functional families, and these profiles were verified as distinct and characteristic. To achieve this result, a scoring function was developed that discriminates between true functional sites and those that are geometrically most similar, but do not perform the same function. In a large-scale retrospective analysis of human genome sequences, this profile score was shown to identify specific functional families correctly. The method is effective at recognizing the likely subtype of structurally uncharacterized members of the diverse family of protein kinases, categorizing sequences correctly that were misclassified by global sequence alignment methods. Subfamily information provided by this three-dimensional active-site profiling method yields key information for specific and selective inhibitor design for use in the pharmaceutical industry.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>14623182</pmid><doi>10.1016/j.jmb.2003.09.062</doi><tpages>15</tpages></addata></record> |
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subjects | active site active-site profile Algorithms Amino Acid Sequence Binding Sites fuzzy functional form Genome, Human Humans Models, Molecular Molecular Sequence Data Protein Folding Protein Structure, Tertiary Proteins - chemistry Proteins - classification Proteins - physiology Sequence Alignment Sequence Homology, Amino Acid structure motifs Structure-Activity Relationship structure-based function annotation |
title | Structure-based Active Site Profiles for Genome Analysis and Functional Family Subclassification |
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