Carla Mattos
Northeastern University, USA
Title: Allosteric modulation of the Ras active site: from biochemistry to binding specificity
Biography
Biography: Carla Mattos
Abstract
Ras is found mutated in about 20% of human cancers, associated with poor prognosis due to a lack of drugs able to deter uncontrolled signaling through multiple pathways in the cell. There are three isoforms: H-, K-, and N-Ras. The G-domain, which catalyzes GTP hydrolysis and mediates downstream signaling, is 95% conserved between the Ras proteins. To date, biochemical studies done on H-Ras have been considered representative of all three Ras proteins. We have recently shown, using a combination of X-ray crystallography, NMR spectroscopy, enzyme kinetic assays and molecular dynamics simulations, that the three isoforms are biochemically distinct due to allosteric effects of isoform-specific residues on the population of conformational states. Furthermore, oncogenic mutations also affect conformational states in the particular isoforms. An engineered high-affinity binder shows a modest specificity toward K-RasG12D over the wild type protein and crystal structures of the complexes reveal allosteric effects on conformational states induced by the mutation, providing a view of specificity features that may be further developed to direct targeting of oncogenic mutants of K-Ras.