12 research outputs found
Comparison of Protein Active Site Structures for Functional Annotation of Proteins and Drug Design
Rapid and accurate functional assignment of novel proteins is increasing in importance, given the completion of numerous genome sequencing projects and the vastly expanding list of unannotated proteins. Traditionally, global primary-sequence and structure comparisons have been used to determine putative function. These approaches, however, do not emphasize similarities in active site configurations that are fundamental to a protein’s activity and highly conserved relative to the global and more variable structural features. The Comparison of Protein Active Site Structures (CPASS) database and software enable the comparison of experimentally identified ligand-binding sites to infer biological function and aid in drug discovery. The CPASS database comprises the ligand-defined active sites identified in the protein data bank, where the CPASS program compares these ligand-defined active sites to determine sequence and structural similarity without maintaining sequence connectivity. CPASS will compare any set of ligand-defined protein active sites, irrespective of the identity of the bound ligand
A Structure-Based Approach for Detection of Thiol Oxidoreductases and Their Catalytic Redox-Active Cysteine Residues
Cysteine (Cys) residues often play critical roles in proteins, for example, in
the formation of structural disulfide bonds, metal binding, targeting proteins
to the membranes, and various catalytic functions. However, the structural
determinants for various Cys functions are not clear. Thiol oxidoreductases,
which are enzymes containing catalytic redox-active Cys residues, have been
extensively studied, but even for these proteins there is little understanding
of what distinguishes their catalytic redox Cys from other Cys functions.
Herein, we characterized thiol oxidoreductases at a structural level and
developed an algorithm that can recognize these enzymes by (i) analyzing amino
acid and secondary structure composition of the active site and its similarity
to known active sites containing redox Cys and (ii) calculating accessibility,
active site location, and reactivity of Cys. For proteins with known or modeled
structures, this method can identify proteins with catalytic Cys residues and
distinguish thiol oxidoreductases from the enzymes containing other catalytic
Cys types. Furthermore, by applying this procedure to Saccharomyces
cerevisiae proteins containing conserved Cys, we could identify the
majority of known yeast thiol oxidoreductases. This study provides insights into
the structural properties of catalytic redox-active Cys and should further help
to recognize thiol oxidoreductases in protein sequence and structure
databases