Structure-based active site profiles for genome analysis and functional family subclassification

Stephen A. Cammer, Brian T. Hoffman, Jeffrey A. Speir, Mary A. Canady, Melanie R. Nelson, Stacy Knutson, Marijo Gallina, Susan M. Baxter, Jacquelyn S. Fetrow

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


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.

Original languageEnglish
Pages (from-to)387-401
Number of pages15
JournalJournal of Molecular Biology
Issue number3
StatePublished - Nov 28 2003


  • Active site
  • Active-site profile
  • Fuzzy functional form
  • Structure motifs
  • Structure-based function annotation


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