The Gur lab has published a new article in JACS Au, a journal of the American Chemical Society, that sheds light on how a promising class of cancer-fighting molecules works at the atomic level. 

“Protein phosphatase 2A (PP2A) is one of the cell’s major ‘brakes’ on signaling, and when it’s suppressed, many cancer-driving pathways can become overactive,” said Associate Professor Mert Gur. 

PP2A acts like a molecular off-switch, keeping cancer-promoting signals in check. Small molecule activators of PP2A, known as SMAPs, have generated excitement because they can restore this tumor-suppressing function. But a key question remained: how do SMAPs first connect with PP2A’s flexible scaffold protein, PR65, and how does that interaction trigger the assembly of the full, active enzyme complex? 

Answering that question was the focus of this study. Using computational methods, the team set out to identify where SMAPs bind PR65 and how that binding shifts PR65 into a shape that supports full enzyme assembly. “The goal was to provide an atomistic, time-resolved mechanistic framework that can guide and prioritize future experiments and structure-based design,” Gur said. 

The project was highly collaborative. Sema (Zeynep) Yilmaz, a postdoctoral fellow in the Gur lab, drove much of the simulation work and analysis. Gur led and coordinated the collaboration and guided the modeling and simulation strategy. The team also partnered with researchers from Stony Brook University, the University of Cambridge, the University of Victoria and Atux Iskay Group, LLC. 

“It was such a joy, and scientifically extremely satisfying, to be able to spearhead a collaborative manuscript with such a great team of outstanding scientists,” Gur said. 

The team’s simulations revealed a step-by-step picture of how SMAPs activate PP2A. The molecules are predicted to first latch onto accessible sites on PR65, nudge the scaffold into a favorable shape, and then settle into a pocket between the enzyme subunits once the full complex assembles. The result is a more active, stable PP2A enzyme. 

These findings carry important implications for cancer drug development. “Reactivating a tumor suppressor enzyme can be approached through scaffold dynamics and holoenzyme assembly, not only through active-site targeting,” Gur said. 

In practical terms, this means future PP2A activators could be designed to target early binding sites on PR65 before the full enzyme even assembles. This could open a new avenue for more precise and selective cancer therapies. 

Gur is enthusiastic about the opportunity to publish in JACS Au, a high-impact, open access journal. His group recently published two papers in Science Advances, where advanced computational work was combined with complementary experimental data through collaboration. What makes this study special is that the JACS Au manuscript is purely computational while still providing a strong mechanistic advance. Read the full article in JACS Au.