Researchers have characterized a complex, little-understood receptor type that, when activated, shuts off hunger. The findings may open up opportunities to fight obesity at the cellular level.

Jens Meiler, of Vanderbilt University, says pharmaceutical companies have long attempted to develop a small-molecule drug that can do just that. But until now, nobody knew exactly what the receptor looked like, making it nearly impossible to design the key to activate it.

The researchers determined the first crystal structure for a neuropeptide Y receptor, deciphering the thousands of carbon, oxygen, nitrogen, and other atoms involved with it and how they bind to one another.

Meiler and a PhD student in his laboratory, Brian J. Bender, translated the inherently low-quality data about the atoms’ coordinates to build accurate computer models of both the inactive receptor and what it looks like when activated.

Binding Keyholes Found

Meiler, a professor of chemistry and pharmacology, said:

“This is a very important milestone in the drug discovery process. The big contribution of this paper is to list the atoms with all the specific coordinates of where they are sitting in space and where they are bound to each other. We’ve actually found where there are little pockets in the structure where we can build a small molecule to bind. Before, it was like trying to design a key without knowing the shape of the keyhole.”

The next step in this molecular-level research is target validation: proving that the receptor really does control hunger. Past studies revealed that when the receptor is blocked from functioning in mice, they become obese.

“Once you eat, you produce this peptide, it activates the receptor, and then you don’t feel hungry anymore and you stop eating,” Meiler said. “The idea here is that we could upregulate this receptor with a small molecule and create this feeling of not being hungry, so that you eat less.”

Meiler said the new paper is part of a much larger, ongoing study that has already produced starting points for the development of potential small-molecule therapeutics.

Zhenlin Yang, et al Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor Nature (2018) doi:10.1038/s41586-018-0046-x

Image: NMR solution structure of Neuropeptide Y. Credit: S. Jähnichen

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