Nanobody-enabled monitoring of kappa opioid receptor states
Abstract
Recent studies show that GPCRs rapidly interconvert between multiple states although our ability to interrogate, monitor and visualize them is limited by a relative lack of suitable tools. We previously reported two nanobodies (Nb39 and Nb6) that stabilize distinct ligand- and efficacy-delimited conformations of the kappa opioid receptor. Here, we demonstrate via X-ray crystallography a nanobody-targeted allosteric binding site by which Nb6 stabilizes a ligand-dependent inactive state. As Nb39 stabilizes an active-like state, we show how these two state-dependent nanobodies can provide real-time reporting of ligand stabilized states in cells in situ. Significantly, we demonstrate that chimeric GPCRs can be created with engineered nanobody binding sites to report ligand-stabilized states. Our results provide both insights regarding potential mechanisms for allosterically modulating KOR with nanobodies and a tool for reporting the real-time, in situ dynamic range of GPCR activity.
- Authors:
-
[1];
[1];
[1];
[1];
[2];
[1];
[3];
[2];
[1]
- Univ. of North Carolina, Chapel Hill, NC (United States)
- Vrije Universiteit Brussel (VUB) (Belgium)
- RTI International, Research Triangle Park, NC (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- National Institutes of Health (NIH)
- OSTI Identifier:
- 1604214
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES
Citation Formats
Che, Tao, English, Justin, Krumm, Brian E., Kim, Kuglae, Pardon, Els, Olsen, Reid H. J., Wang, Sheng, Zhang, Shicheng, Diberto, Jeffrey F., Sciaky, Noah, Carroll, F. Ivy, Steyaert, Jan, Wacker, Daniel, and Roth, Bryan L. Nanobody-enabled monitoring of kappa opioid receptor states. United States: N. p., 2020.
Web. doi:10.1038/s41467-020-14889-7.
Che, Tao, English, Justin, Krumm, Brian E., Kim, Kuglae, Pardon, Els, Olsen, Reid H. J., Wang, Sheng, Zhang, Shicheng, Diberto, Jeffrey F., Sciaky, Noah, Carroll, F. Ivy, Steyaert, Jan, Wacker, Daniel, & Roth, Bryan L. Nanobody-enabled monitoring of kappa opioid receptor states. United States. https://doi.org/10.1038/s41467-020-14889-7
Che, Tao, English, Justin, Krumm, Brian E., Kim, Kuglae, Pardon, Els, Olsen, Reid H. J., Wang, Sheng, Zhang, Shicheng, Diberto, Jeffrey F., Sciaky, Noah, Carroll, F. Ivy, Steyaert, Jan, Wacker, Daniel, and Roth, Bryan L. Mon .
"Nanobody-enabled monitoring of kappa opioid receptor states". United States. https://doi.org/10.1038/s41467-020-14889-7. https://www.osti.gov/servlets/purl/1604214.
@article{osti_1604214,
title = {Nanobody-enabled monitoring of kappa opioid receptor states},
author = {Che, Tao and English, Justin and Krumm, Brian E. and Kim, Kuglae and Pardon, Els and Olsen, Reid H. J. and Wang, Sheng and Zhang, Shicheng and Diberto, Jeffrey F. and Sciaky, Noah and Carroll, F. Ivy and Steyaert, Jan and Wacker, Daniel and Roth, Bryan L.},
abstractNote = {Recent studies show that GPCRs rapidly interconvert between multiple states although our ability to interrogate, monitor and visualize them is limited by a relative lack of suitable tools. We previously reported two nanobodies (Nb39 and Nb6) that stabilize distinct ligand- and efficacy-delimited conformations of the kappa opioid receptor. Here, we demonstrate via X-ray crystallography a nanobody-targeted allosteric binding site by which Nb6 stabilizes a ligand-dependent inactive state. As Nb39 stabilizes an active-like state, we show how these two state-dependent nanobodies can provide real-time reporting of ligand stabilized states in cells in situ. Significantly, we demonstrate that chimeric GPCRs can be created with engineered nanobody binding sites to report ligand-stabilized states. Our results provide both insights regarding potential mechanisms for allosterically modulating KOR with nanobodies and a tool for reporting the real-time, in situ dynamic range of GPCR activity.},
doi = {10.1038/s41467-020-14889-7},
journal = {Nature Communications},
number = 1,
volume = 11,
place = {United States},
year = {Mon Mar 02 00:00:00 EST 2020},
month = {Mon Mar 02 00:00:00 EST 2020}
}
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