Selective G protein signaling driven by substance P-neurokinin receptor dynamics

Julian A Harris; Bryan Faust; Arisbel B Gondin; Marc André Dämgen; Carl-Mikael Suomivuori; Nicholas A Veldhuis; Yifan Cheng; Ron O Dror; David M Thal; Aashish Manglik

doi:10.1038/s41589-021-00890-8

Selective G protein signaling driven by substance P-neurokinin receptor dynamics

Nat Chem Biol. 2022 Jan;18(1):109-115. doi: 10.1038/s41589-021-00890-8. Epub 2021 Oct 28.

Authors

Julian A Harris^#^{1

2}, Bryan Faust^#^{1

3

4}, Arisbel B Gondin^#^{5

6}, Marc André Dämgen^#^{7

8

9

10}, Carl-Mikael Suomivuori^{7

8

9

10}, Nicholas A Veldhuis^{5

6}, Yifan Cheng^{11

12}, Ron O Dror^{13

14

15

16}, David M Thal¹⁷, Aashish Manglik^{18

19}

Affiliations

¹ Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
² Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, CA, USA.
³ Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
⁴ Biophysics Graduate Program, University of California, San Francisco, CA, USA.
⁵ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
⁶ Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Victoria, Australia.
⁷ Department of Computer Science, Stanford University, Stanford, CA, USA.
⁸ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
¹¹ Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA. [email protected].
¹² Howard Hughes Medical Institute, University of California, San Francisco, CA, USA. [email protected].
¹³ Department of Computer Science, Stanford University, Stanford, CA, USA. [email protected].
¹⁴ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
¹⁵ Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
¹⁶ Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA. [email protected].
¹⁷ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. [email protected].
¹⁸ Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA. [email protected].
¹⁹ Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA. [email protected].

^# Contributed equally.

Abstract

The neuropeptide substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via G_q and G_s proteins. Neurokinin A also activates NK1R, but leads to selective G_q signaling. How two stimuli yield distinct G protein signaling at the same G protein-coupled receptor remains unclear. We determined cryogenic-electron microscopy structures of active NK1R bound to SP or the G_q-biased peptide SP6-11. Peptide interactions deep within NK1R are critical for receptor activation. Conversely, interactions between SP and NK1R extracellular loops are required for potent G_s signaling but not G_q signaling. Molecular dynamics simulations showed that these superficial contacts restrict SP flexibility. SP6-11, which lacks these interactions, is dynamic while bound to NK1R. Structural dynamics of NK1R agonists therefore depend on interactions with the receptor extracellular loops and regulate G protein signaling selectivity. Similar interactions between other neuropeptides and their cognate receptors may tune intracellular signaling.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
GTP-Binding Proteins / metabolism*
Inflammation / metabolism
Receptors, Neurokinin-1 / metabolism*
Signal Transduction*

Substances

Receptors, Neurokinin-1
GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding