Modulating Guanosine Triphosphate Hydrolysis Provides Novel Therapeutic Option to Treat Cancer and Bacterial Infections

Project Overview

GTPases are a family of proteins that function as molecular switches to regulate many signal pathways and malfunction of these proteins frequently cause human diseases, including cancer and bacterial infections. Despite the importance of these proteins, they are famously known as undruggable because of a lack of apparent drug binding pockets. By leveraging the supercomputing power at Lawrence Livermore National Laboratory (LLNL), we implemented molecular dynamics (MD) to study the conformational dynamics of these proteins in order to identify new druggable pockets and new therapeutics opportunities.

Within this LDRD, we have systematically studied the catalytic mechanism of wildtype KRas, one of the most important GTPase protein associated with ~30% of human cancers, and its cancer-causing mutants. We also identified a novel pocket near its active site and proved ligand binding into this pocket could restore normal activity for KRas mutants through collaborating with UCSF experimental group. Furthermore, together with UCSF collaborators, we identified a conserved allosteric pocket in multiple GTPase proteins and hit molecules specific to different proteins.

Mission Impact

Rapid response in medical countermeasures is the core of Bio-Resilience Mission Focus Area (MFA). To enable rapid bio-countermeasures, being able to quickly identify binding pocket and hit molecules, especially those difficult to be identified experimentally, are essential. We developed tools and capabilities to meet such challenges. Such tools will enable LLNL to create new ways of responding national biosecurity challenges.

Publications, Presentations, and Patents

Morstein, Johannes, Yue Yang, Micah Fernando, Lawrence Zhu, Victoria Bowcut, Meredith L. Jenkins, John T. Evans, Keelan Z. Guiley, D. Matthew Peacock, John E. Burke, Felice C. Lightstone, and Kevan M. Shokat. "Targeting Ras-, Rho-, and Rab-Family GTPases via a Conserved Cryptic Pocket." Cell, under revision.