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Seeing the Once Un-seeable

TRPV2 bound with CBD.

The cover of the May 19th issue of New York Times Magazine depicted a giant green gummy bear. Twenty arrows emanated from its body, labelled with an array of medical conditions from anxiety to cancer. The article it teased, “Can CBD Really do All That?,” is one of many in recent months to contemplate the medical value of cannabidiol (CBD), the non-addictive active ingredient of marijuana, and the chemical cousin of the psychoactive component THC. In fact, last week the U.S. Food and Drug Administration (FDA) held the first public hearing on CBD to wade through a quagmire of wellness claims, science, and regulatory confusion about the substance. FDA commissioner Ned Sharpless summed up the current state of knowledge about CBD biology in STAT News: “While we have seen an explosion of interest in products containing CBD, there is still much that we don’t know.”

That’s where structural biologists and a 2017 Nobel Prize-winning, uber-cool microscopic technique come in—by improving our view of key molecules needed answer basic biological questions. A trio of veteran biochemists received the Nobel in Chemistry "for developing cryo-electron microscopy [cryo-EM] for the high-resolution structure determination of biomolecules in solution." That short technical description is the core of Penn’s new Beckman Center for Cryo-EM, which held its ribbon cutting and inaugural symposium in late May.

Cryo-EM uses an electron beam to take thousands of snapshots of protein molecules—from, for example, a cell’s outer membrane or deep inside the nucleus—flash frozen in a thin layer of water. Algorithms then combine the multiple images to sharpen the overall picture of the molecules’ structure. Getting a look at cells in a sharper, deeper way has improved scientists’ understanding of a range of human functions, from how kidney stones form to the connection between a breast cancer protein and lupus. Cryo-EM is even on the cusp of helping scientists better understand how CBD and other natural products interact with neurons and other cells in the body. These insights could improve the treatment of cancer, heart disease, and kidney disorders.

Advances in cameras and processing speed have heightened expectations that cryo-EM might become an important tool for drug discovery. Developing new medicines, or getting a better handle on why old ones work the way they do, starts with tweaking a molecule’s shape to improve its effectiveness. In many cases, the proverbial cryo-EM image that’s worth a thousand words is a never-before achieved three-dimensional picture of a potential drug bound with its target.

Cryo-EM uncovers atomic structures that are currently beyond the reach of such traditional techniques as X-ray crystallography and nuclear magnetic resonance, which have significant limitations, for instance in image clarity compared to cryo-EM. “It’s a high-end instrument we use to determine the atomic structure of complex protein units as they exist in their natural cellular environment,” said Ronen Marmorstein, PhD, a professor of Biochemistry and Biophysics, and principal investigator on the 2017 grant that established Penn’s Beckman Center.

The research of Vera Moiseenkova-Bell, PhD, a professor of Systems Pharmacology and Translational Therapeutics and faculty director of the Center, concentrates on the structure and function of transient receptor potential (TRP) channels, which have been implicated in pain sensation, neuronal development, cardiovascular and renal diseases, and cancer. TRPs span the outer membrane of many cell types to bind with molecules that guide cellular function, by forming channels, or tunnels, that allow the flow of ions like calcium in and out of a cell. This seemingly simple function is the basis of a cell’s energy and serves as the method by which nerve cells communicate. Moiseenkova-Bell’s lab has made cryo-EM channel images, for example, depicting the opening and closing of a kidney cell channel to extract calcium from urine.

More recently, the lab has started to tackle how another type of TRP channel binds with CBD. In preliminary research, the team determined different views of the structure of the full-length TRPV2 channel bound to CBD. They found that the channel changes shape upon binding with CBD, eventually leading it to open, which is giving her team insights into how CBD works in the brain. This line of research may already have important applications because last summer the FDA approved Epidiolex, an oral CBD medication for treating seizures associated with two rare and severe forms of epilepsy.

“Although we are still refining the details of our images, this is a clear example of how cryo-EM gives us an unprecedented view of a significant compound such as CBD binding to a human protein,” Moiseenkova-Bell said. “Other TRP channels have been shown to bind cannabinoids. Expanding our knowledge of how these substances bind to this diverse family of ion channels can teach us how to design new and better CBD-based drugs.” This information will be applied to better understanding how cannabinoids and other drugs affect ion channels’ influence on activating or deactivating downstream reactions inside a cell.

Although Sharpless’s comment about how much is left to uncover about CBD may be true for the near future, thanks to Moiseenkova-Bell’s cryo-EM research, we are getting closer to a sharper overall picture.


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