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
Hauptverfasser: 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.
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container_end_page 401
container_issue 3
container_start_page 387
container_title Journal of molecular biology
container_volume 334
creator 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.
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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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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