1) How did you compose this image?
This image was created by Lorenzo Casalino, a postdoctoral scholar in my lab. The image was composed using VMD 1.9.3 starting from the PDB of the CTX-M-9 beta-lactamase (PDB code: 1YlJ) and rendered by the built-in Tachyon ray tracer. The image has been subsequently manipulated using Photos by Apple Inc. and Adobe Photoshop CC to introduce and model the glow effect around C69 and surrounding residues.
2) How does this image reflect your scientific research?
We and others are often in search of hidden pockets in proteins. These pockets can be important for understanding ligand binding and protein interactions or be novel druggable sites. The image shows one such novel cryptic pocket, newly discovered by Bowman and colleagues and discussed in their paper, which is highlighted with a New and Notable. We made the pocket glow to indicate that it’s in a special place on the surface of the protein.
3) Can you please provide a few real-world examples of your research?
One good example that is related to cryptic allosteric sites is our work in p53. We discovered a novel cryptic allosteric pocket and discovered an inhibitor that used that site to reactivate p53, which is well-known tumor suppressor protein that is dysfunctional in over 50% of human cancers.
Another example of our work shows how we can now build detailed molecular models, at scales never before realized, and then interrogate their structure/ function/ dynamics using physics-based simulation. We did just that with influenza, where we predicted that the secondary site may be an important area for pharmaceutical intervention.
4) How does your research apply to those who are not working in your specific field?
When cryptic pockets are also druggable pockets, the ultimate impact of such work can be wide spread. Armed with this new structural information, teams of researchers can subsequently go on to target these sites with small molecule compounds, to modulate the activity of the drug target for therapeutic gain.
5) Do you have a website where our readers can view your recent research?
Yes, the lab website and two centers: NBCR and Drug Design Data Research.
- Rommie Amaro