Structural and Functional Examination of Inoside Monophosphate Dehydrogenase Using Comparative Protein Analysis

Aligning sequences from homologous proteins can be extremely useful in obtaining insights into conserved features within a protein family and facilitate the construction of structure-function relationships. Assuming similar structure and hence function based on sequence similarity is made possible by the well documented trend that a protein's structure is more conserved than its sequence (Marti-Renom et. al 292). By identifying crucial conserved regions, motifs, and domains, as well as specific residues which are consistently observed among the analyzed proteins, an optimized multiple sequence alignment can be used to obtain valuable information about the protein including secondary and tertiary structure prediction, residue accessibility and function, and relative importance of certain residues and regions which give the protein its distinct functionality (Barton 215). Furthermore, accurate sequence alignments are critical to constructing 3-D models of proteins within the family that have unknown structure through homology modeling. Knowledge of the protein structure either through experiment or through modeling can then facilitate the modeling of inhibitors into the active site through computational docking. Analysis of docked structures with respect to residues identified as critical through the sequence-based bioinformatics increases the power of the structure-function relationship. One protein which is a particularly good candidate for comparative sequence analysis is the enzyme inosine monophosphate dehydrogenase (IMPDH). Enzymes which catalyze nucleotide biosynthesis are critically essential in allowing cells to proliferate because nucleotides are necessary for DNA synthesis. The unique initial step in guanine nucleotide synthesis is catalyzed by IMPDH (Zhang et. al 4691). Also, guanosine triphosphate, which is a direct successor of guanine, has an important role in intracellular signaling and as a source of energy