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Title: Crystal structure of the human NK1 tachykinin receptor

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. Furthermore, the structure of hNK1R is a valuable tool in the further development of tachykinin receptor modulators for multiple clinical applications.

Authors:
 [1];  [1];  [1];  [1]; ORCiD logo [1];  [2];  [3]; ORCiD logo [1]
  1. The Univ. of Texas Southwest Medical Center, Dallas, TX (United States)
  2. Argonne National Lab. (ANL), Argonne, IL (United States)
  3. Univ. of Pittsburgh, Pittsburgh, PA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
Welch Foundation; National Institutes of Health (NIH); USDOE
OSTI Identifier:
1493430
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 115; Journal Issue: 52; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; GPCR; drug design; ligand recognition; substance P; tachykinin receptor

Citation Formats

Yin, Jie, Chapman, Karen, Clark, Lindsay D., Shao, Zhenhua, Borek, Dominika, Xu, Qingping, Wang, Junmei, and Rosenbaum, Daniel M. Crystal structure of the human NK1 tachykinin receptor. United States: N. p., 2018. Web. doi:10.1073/pnas.1812717115.
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. United States. doi:10.1073/pnas.1812717115.
Yin, Jie, Chapman, Karen, Clark, Lindsay D., Shao, Zhenhua, Borek, Dominika, Xu, Qingping, Wang, Junmei, and Rosenbaum, Daniel M. Tue . "Crystal structure of the human NK1 tachykinin receptor". United States. doi:10.1073/pnas.1812717115. https://www.osti.gov/servlets/purl/1493430.
@article{osti_1493430,
title = {Crystal structure of the human NK1 tachykinin receptor},
author = {Yin, Jie and Chapman, Karen and Clark, Lindsay D. and Shao, Zhenhua and Borek, Dominika and Xu, Qingping and Wang, Junmei and Rosenbaum, Daniel M.},
abstractNote = {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. Furthermore, the structure of hNK1R is a valuable tool in the further development of tachykinin receptor modulators for multiple clinical applications.},
doi = {10.1073/pnas.1812717115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 52,
volume = 115,
place = {United States},
year = {2018},
month = {12}
}

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