Crystal structure of the human NK1 tachykinin receptor

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

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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 (hNK1R) modulators have shown promise in clinical trials for migraine, 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 molecular-dynamics 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.

Original languageEnglish (US)
Pages (from-to)13264-13269
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number52
DOIs
StatePublished - Dec 26 2018

Fingerprint

Tachykinin Receptors
aprepitant
L 760735
Vomiting
Depression
Physiological Phenomena
Neurokinin-1 Receptors
Tachykinins
Nociception
Molecular Dynamics Simulation
Drug Delivery Systems
Substance P
Neuropeptides
Migraine Disorders
Nausea
Mammals
Clinical Trials
Ligands
Inflammation
Drug Therapy

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Crystal structure of the human NK1 tachykinin receptor. / Yin, Jie; Chapman, Karen; Clark, Lindsay D.; Shao, Zhenhua; Borek, Dominika; Xu, Qingping; Wang, Junmei; Rosenbaum, Daniel M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 52, 26.12.2018, p. 13264-13269.

Research output: Contribution to journalArticle

Yin, Jie ; Chapman, Karen ; Clark, Lindsay D. ; Shao, Zhenhua ; Borek, Dominika ; Xu, Qingping ; Wang, Junmei ; Rosenbaum, Daniel M. / Crystal structure of the human NK1 tachykinin receptor. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 52. pp. 13264-13269.
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