Crystal structure of the human NK 1 tachykinin receptor

Jie Yin, Karen Chapman, Lindsay D. Clark, Zhenhua Shao, Dominika Borek, Qingping Xu, Junmei Wang, Daniel M Rosenbaum

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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 languageEnglish (US)
Pages (from-to)13264-13269
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number52
StatePublished - Dec 26 2018


  • Drug design
  • GPCR
  • Ligand recognition
  • Substance P
  • Tachykinin receptor

ASJC Scopus subject areas

  • General


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