From Atoms to Organoids: Understanding the Conformational Landscape and Regulation of Small GTPases
Dr. Fatema Bhinderwala, a postdoc in the department of structural biology in Dr. Angela Gronenborn’s lab, has been awarded a prestigious NIH K99/R00 Pathway to Independence Award, supporting the transition to an independent research career.
This project focuses on understanding how oncogenic RhoA, a member of the small GTPase family, is regulated and misregulated in cancer. While small GTPases act as molecular switches that control critical signaling pathways, key gaps remain in understanding how these proteins function in their native cellular environments. Notably, RhoA exhibits a unique regulatory mechanism through its interaction with RhoGDI, which sequesters the inactive form of the protein and modulates its activity.
To address these challenges, this work integrates advanced structural biology and biophysical approaches, including ¹⁹F in-cell NMR, in-cell NMR, and time-resolved crystallography, with patient-derived organoid models. This combined strategy enables investigation of RhoA activity and protein interactions at atomic resolution within physiologically relevant cancer systems.
The project will (1) define the mechanism of GTP hydrolysis in RhoA and its oncogenic mutants, (2) determine how cellular and tumor environments influence RhoA activity and protein–ligand interactions, and (3) identify new therapeutic opportunities by targeting the RhoA–RhoGDI interaction, including the discovery of transient binding pockets and candidate ligands in organoid models.
This work aims to advance fundamental understanding of small GTPase biology while establishing new tools to study signaling proteins in disease-relevant systems, with the long-term goal of enabling novel therapeutic strategies for cancer.