Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity

Manbir Sandhu (), Aaron Cho, Ning Ma, Elizaveta Mukhaleva, Yoon Namkung, Sangbae Lee, Soumadwip Ghosh, John H. Lee, David E. Gloriam, Stéphane A. Laporte, M. Madan Babu () and Nagarajan Vaidehi ()
Additional contact information
Manbir Sandhu: Beckman Research Institute of the City of Hope
Aaron Cho: Research Institute of the McGill University Health Centre
Ning Ma: Beckman Research Institute of the City of Hope
Elizaveta Mukhaleva: Beckman Research Institute of the City of Hope
Yoon Namkung: Research Institute of the McGill University Health Centre
Sangbae Lee: Beckman Research Institute of the City of Hope
Soumadwip Ghosh: Beckman Research Institute of the City of Hope
John H. Lee: Beckman Research Institute of the City of Hope
David E. Gloriam: University of Copenhagen
Stéphane A. Laporte: Research Institute of the McGill University Health Centre
M. Madan Babu: Center for Data Driven Discovery, St. Jude Children’s Research Hospital
Nagarajan Vaidehi: Beckman Research Institute of the City of Hope

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Recent studies have shown that G protein coupled receptors (GPCRs) show selective and promiscuous coupling to different Gα protein subfamilies and yet the mechanisms of the range of coupling preferences remain unclear. Here, we use Molecular Dynamics (MD) simulations on ten GPCR:G protein complexes and show that the location (spatial) and duration (temporal) of intermolecular contacts at the GPCR:Gα protein interface play a critical role in how GPCRs selectively interact with G proteins. We identify that some GPCR:G protein interface contacts are common across Gα subfamilies and others specific to Gα subfamilies. Using large scale data analysis techniques on the MD simulation snapshots we derive a spatio-temporal code for contacts that confer G protein selective coupling and validated these contacts using G protein activation BRET assays. Our results demonstrate that promiscuous GPCRs show persistent sampling of the common contacts more than G protein specific contacts. These findings suggest that GPCRs maintain contact with G proteins through a common central interface, while the selectivity comes from G protein specific contacts at the periphery of the interface.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-34055-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34055-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-34055-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().