An international team has uncovered the potential to beat obesity at the cellular level, characterizing for the first time a complex, little-understood receptor type that, when activated, shuts off hunger.
The team 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.
They 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. Human Y1R bound to the two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 Å resolution were characterized.
"This is a very important milestone in the drug discovery process," author said. "The big contribution of this paper is to list the atoms with all the specific coordinates of where they 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."
Their findings are published in the journal Nature.
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," another author 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."
https://news.vanderbilt.edu/2018/04/18/characterizing-keyhole-is-first-step-to-fighting-obesity-at-the-cellular-level/
https://www.nature.com/articles/s41586-018-0046-x
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