Rafael Najmanovich
Talk Title :
The role of evolutionarily conserved ligand-interacting binding-site residues
Date / Time / Location:
Thursday,December 10th 2009 - 6:00 pm
McGill University
Room 232, Leacock Building
855 Sherbrooke Street West
Affiliation :
Université Sherbrooke
Abstract :
Evolutionarily conserved ligand-interacting binding-site residues are thought to be important to satisfy physico-chemical binding constraints. Recently we demonstrated that non-homologous proteins that evolved to bind similar ligands contain highly dissimilar patterns of conserved ligand-interacting binding-site residues. While the importance of conserved residues is unquestionable, these results suggest that conserved residues may play extra roles. We suggest that conserved residues may play the additional role of preventing the promiscuous binding of similar molecules present in the cellular milieu. Different patterns of conservation would reflect distinct cellular contexts. In support of this hypothesis, we created a dataset (and associated web-interface) of proteins with known structures containing binding site mutations in which both the wild type and mutant were crystallized with the ligand (as well as sometimes in the Apo form) demonstrating that the mutation does not prevent ligand binding. The dataset includes over 5000 entries containing between one and four mutations on residues with varying degrees of conservation in contact with ligands with varying levels of cognate similarity. Due to the experimental bias towards mutations on highly conserved residues, there are numerous cases of often-drastic changes on highly conserved residues bound to cognate ligands. If such drastic mutations do not prevent binding, the conserved residues in question must have a different essential function, including that of preventing promiscuity among other possibilities.