‘Molecular library’ opens up new frontier of biological space-time

By Jon Atherton

In the search for solutions to diseases like cancer, scientists are pursuing a new frontier in biology – the spatial and temporal places where our cells live.

Where first generation drugs targeted single molecules, over time evolving their own resistance, new tools and techniques are needed to keep ahead of resistant diseases by targeting the surrounding cellular space. 

Much of this exploration is taking place at the surface of our cells – the protein packed semi-permeable membranes that act as protectors and as signaling posts to other cells in the surrounding area. 

Over 60% of current market drugs target our membrane proteins, and this number is expected to increase with the help of a new, accessible molecular ‘library’ developed by Yale’s Kallol Gupta, an assistant professor of Cell Biology at the School of Medicine. 

“There are all kinds of proteins congregating at the cellular membrane, and if we want to understand what a protein does, how it’s regulated by its environment, and specifically how it triggers the spread of a disease, we need to understand what surrounds it,” explained Gupta, whose lab is part of the Nanobiology Institute at Yale’s West Campus. 

Lacking the spatial nanotechnology required to understand the molecular context of how membrane proteins are regulated in health and diseases, the scholars developed a novel platform that provides access to around 2000 membrane proteins as well as a chemical tool to examine areas that surround proteins of interest.

“We wanted to share these important tools to study membrane proteins and make them accessible to researchers anywhere in the world,” said Caroline Brown, a graduate student in the Gupta lab and a co-first author of the study, which appears in Nature Methods..

“There are thousands of proteins in our body, but which one should you look at relative to a specific disease?”  

- Caroline Brown

The new database is expected to save time by helping any researcher trying to find proteins that relate to a specific health problem.

Collaborating with adjacent labs at the West Campus, the scholars used on-site mass spectrometry to reveal a class of molecules known to be active at the cell membrane.

With the ‘library’ established, the scholars turned to developing a new tool that could make sense of the broader cellular space. 

Typically measured at the micron level – or slightly thinner than a spider web – for the library to reveal events and associations driving protein signaling, resolutions of a thousand-fold higher would be needed. 

“By modulating the chemistry of the molecules, we were able to change the diameter of the area of interest to create a new spatial resolution that helps us understand how the function of a protein is regulated by its surroundings,” continued Gupta. 

The result is what the scientists refer to as a programmable chemical ‘scoop’ used to collect molecular information from a given nanoscale contextual area. 

The technological landmark is expected to help more scientists understand how membrane proteins interact in association with other proteins, in turn revealing new drug targets to disrupt the spatial signals that drive different diseases.

The Gupta Lab’s Snehasish Ghosh was co-first author, with contributors from the labs of Moitrayee Bhattacharyya, James Rothman, and Yansheng Liu at the Yale Cancer Biology Institute, and colleagues in the departments of Cell Biology and Pharmacology.