Stetten Lecturer Amaro Sheds Light on Shape-Shifting Proteins
Scientists have long sought to visualize the detailed structures and movements of proteins in real time within living cells.
This year’s DeWitt Stetten Jr. Lecture will feature one of the leaders in this emerging field: Dr. Rommie Amaro, a professor in the department of chemistry and biochemistry at the University of California, San Diego. Her talk is titled “Computing Cures: Discovery Through the Lens of a Computational Microscope.” The lecture will occur on Wednesday, Oct. 25 at 3 p.m. in Masur Auditorium, Bldg. 10. It is sponsored by NIGMS and is part of the NIH Director’s Wednesday Afternoon Lecture Series.
For decades, scientists have captured the detailed, 3-dimensional images of crystallized proteins. These images have provided invaluable information about thousands of proteins. But they show proteins only in one position—paralyzed unnaturally within a crystal.
State-of-the-art cellular imaging techniques allow researchers to see the movement of individual molecules within a cell. But currently, the tools can only track rather slow movements, not the flip of a protein from one form to another, which occurs in trillionths of a second.
Amaro and her colleagues are combining existing techniques and developing new ones to create detailed images of proteins as they move and morph. The scientists then validate the accuracy of their computational predictions using laboratory experiments.
The work promises to deepen our understanding of the ever-active world within cells. It might also point the way to new treatments for countless diseases. For example, the simulations might indicate a way to restore the normal functioning of a protein that, when faulty, causes disease. That’s the goal of one of Amaro’s projects. She focuses on the p53 protein.
A major function of p53 is to prevent cancer. Normal versions of p53 detect damaged DNA—which can cause cancer—and prevent it from being passed on to a new generation of cells.
In its active form, four molecules of p53 are linked together into a structure called a tetramer. The p53 tetramer acts as a clamp that grabs onto specific genes and shuts down cell division. By blocking cell division, p53 prevents any DNA mutations from being passed to a new generation of cells.
When p53 isn’t working properly, cells are at high risk for cancer. Defective versions of p53 are associated with more human cancers—about 50 percent of them—than any other malfunctioning protein. As a result, many researchers, including Amaro, seek to reactivate mutant p53 as a way to develop new anti-cancer treatments.
By simulating the movements of p53, Amaro and her team identified a pocket in the protein’s core that only opens when the protein’s shape shifts. Finding this pocket helped to explain how a potential new drug, now in clinical trials, produces its anti-cancer effect. Amaro and her colleagues suspected that the pocket might also provide a foothold for a small molecule that could restore function to mutant p53 proteins.
To see if they could find such a therapeutic small molecule, Amaro and her group computationally tested thousands of small molecules, analyzing the ability of each to fit into p53’s pocket. The scientists then conducted laboratory experiments on 45 of the molecules that, based on computational predictions, appeared most likely to bind in the pocket.
Based on these experiments, one small molecule stood out as having the greatest potential to rehabilitate cancer-causing mutant p53. Building on this discovery, Amaro and her team developed dozens of small molecules that reactivated p53. This work formed the basis for a biotech startup, Actavalon, Inc., to translate these findings into a new anti-cancer drug.
Amaro’s team is beginning to model the movements of ever larger and more flexible structures. Recently, her group simulated how p53 behaves as a tetramer bound to different sequences of DNA. This work showed how p53 can change its “grip” on DNA depending on the DNA sequence. The project also revealed the roles of all portions of the p53 molecule. This information sheds light on how p53 does its job and opens new avenues for drug discovery.
Amaro leads two NIGMS-supported resources at UCSD. She directs the National Biomedical Computation Resource and co-directs the Drug Design Data Resource.
Amaro received her B.S. in chemical engineering in 1999 and her Ph.D. in chemistry in 2005, both from the University of Illinois, Urbana-Champaign.
In 2016, Amaro was named the American Chemical Society Kavli Emerging Leader in Chemistry and also received the Corwin Hansch Award, which is given annually to a scientist under the age of 40 who contributes significantly to the field of computer-aided drug design. Amaro also received a 2010 Presidential Early Career Award for Scientists and Engineers and a 2010 NIH Director’s New Innovator Award.
For more information on the lecture or for reasonable accommodation, contact Jacqueline Roberts at Jacqueline.Roberts@nih.gov or (301) 594-6747.