Abstract
The NK 1 tachykinin G-protein–coupled receptor (GPCR) binds substance P, the first neuropeptide to be discovered in mammals. Through activation of NK 1 R, substance P modulates a wide variety of physiological and disease processes including nociception, inflammation, and depression. Human NK 1 R (hNK 1 R) modulators have shown promise in clinical trials for migraine, depression, and emesis. However, the only currently approved drugs targeting hNK 1 R are inhibitors for chemotherapy-induced nausea and vomiting (CINV). To better understand the molecular basis of ligand recognition and selectivity, we solved the crystal structure of hNK 1 R bound to the inhibitor L760735, a close analog of the drug aprepitant. Our crystal structure reveals the basis for antagonist interaction in the deep and narrow orthosteric pocket of the receptor. We used our structure as a template for computational docking and molecular-dynamics simulations to dissect the energetic importance of binding pocket interactions and model the binding of aprepitant. The structure of hNK 1 R is a valuable tool in the further development of tachykinin receptor modulators for multiple clinical applications.
Original language | English (US) |
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Pages (from-to) | 13264-13269 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 115 |
Issue number | 52 |
DOIs | |
State | Published - Dec 26 2018 |
Keywords
- Drug design
- GPCR
- Ligand recognition
- Substance P
- Tachykinin receptor
ASJC Scopus subject areas
- General