Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 52, Pages 13264-13269Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1812717115
Keywords
GPCR; tachykinin receptor; substance P; drug design; ligand recognition
Categories
Funding
- Edward Mallinckrodt, Jr. Foundation Scholar Award
- Welch Foundation [I-1770]
- National Institutes of Health [R01-GM117080, R01-GM079383, R21-GM097617, R01-NS103939]
- DOE Office of Science [DE-AC02-06CH11357]
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The NK1 tachykinin G-protein-coupled receptor (GPCR) binds substance P, the first neuropeptide to be discovered in mammals. Through activation of NK1R, substance P modulates a wide variety of physiological and disease processes including nociception, inflammation, and depression. Human NK1R (hNK 1 R) modulators have shown promise in clinical trials formigraine, depression, and emesis. However, the only currently approved drugs targeting hNK1R 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 hNK1R 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 moleculardynamics simulations to dissect the energetic importance of binding pocket interactions and model the binding of aprepitant. The structure of hNK1R is a valuable tool in the further development of tachykinin receptor modulators for multiple clinical applications.
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