Structural and Functional Analysis of a β2-Adrenergic Receptor Complex with GRK5
Open accessAbstract
The phosphorylation of agonist-occupied G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) functions to turn off G-protein signaling and turn on arrestin-mediated signaling. While a structural understanding of GPCR/G-protein and GPCR/arrestin complexes has emerged in recent years, the molecular architecture of a GPCR/GRK complex remains poorly defined. We used a comprehensive integrated approach of cross-linking, hydrogen-deuterium exchange mass spectrometry (MS), electron microscopy, mutagenesis, molecular dynamics simulations, and computational docking to analyze GRK5 interaction with the β 2-adrenergic receptor (β 2 AR). These studies revealed a dynamic mechanism of complex formation that involves large conformational changes in the GRK5 RH/catalytic domain interface upon receptor binding. These changes facilitate contacts between intracellular loops 2 and 3 and the C terminus of the β 2 AR with the GRK5 RH bundle subdomain, membrane-binding surface, and kinase catalytic cleft, respectively. These studies significantly contribute to our understanding of the mechanism by which GRKs regulate the function of activated GPCRs. PAPERCLIP.
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The structure of the phosphorylated human neurotensin receptor 1 with arrestin reveals a PI(4,5)P2 molecule forming a bridge between the receptor and arrestin.
“The structure of the phosphorylated human neurotensin receptor 1 with arrestin reveals a PI(4,5)P2 molecule forming a bridge between the receptor and arrestin [120,121].”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [120]
The Abstract and the Results and Discussion section on receptor activation and acidic lipids examine PIP2 in a β2-adrenergic receptor–GRK5 complex. Searches for neurotensin receptor 1 and a PIP2 bridge to arrestin found no passage in our copy addressing the claimed structure. The paper’s different complex does not, by itself, contradict the claim. (LLM, conf=0.76)
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Self-citationStructure of the neurotensin receptor 1 in complex with β-arrestin 1
Huang, W., Masureel, M., Qu, Q., Janetzko, J., Inoue, A., Kato, H. E., Robertson, M. J., Nguyen, K. C., Glenn, J. S., Skiniotis, G., et al. (2020) · Nature · doi:10.1038/s41586-020-1953-1 · Cited by 373 · see citing works
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Structures of rhodopsin in complex with G-protein-coupled receptor kinase 1
Chen, Q., Plasencia, M., Li, Z., Mukherjee, S., Patra, D., Chen, C.-L., Klose, T., Yao, X.-Q., Kossiakoff, A. A., Chang, L., et al. (2021) · Nature · doi:10.1038/s41586-021-03721-x · Cited by 152 · see citing works
Self-citation
- Authors
- Komolov, K. E., Du, Y., Duc, N. M., Betz, R. M., Rodrigues, J. P. G. L. M., Leib, R. D., Patra, D., Skiniotis, G., Adams, C. M., Dror, R. O., Chung, K. Y., Kobilka, B. K., & Benovic, J. L.
- Affiliations
- Thomas Jefferson University (US)
- Stanford Medicine (US)
- Sungkyunkwan University (KR)
- University of Michigan (US)
- Corresponding author
- Kobilka, Brian K.
- Benovic, Jeffrey L.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 169
- Issue
- 3
- Pages
- 407-421.e16
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5526774
- OpenAlex
- W2605880739
- Cited by
- 152
- References
- 0
- Citations by year
- 2026: 13 · 2025: 7 · 2024: 8 · 2023: 11 · 2022: 14 · 2021: 17 · 2020: 24 · 2019: 26 · 2018: 26 · 2017: 6
- FWCI
- 8.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Medicine Forum (submittedVersion)
- Funders
- National Institutes of Health (P01HL114471, R01GM068857, R01GM083118, R01NS028571)
- G. Harold and Leila Y. Mathers Charitable Foundation
- Stanford University
- National Research Foundation of Korea (NFR-2015R1A1A1A05027473, NRF-2012R1A5A2A28671860)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- beta2-adrenergic receptor, GRK5, GPCR kinases, catalytic domain, conformational change, intracellular loop, arrestin signaling, hydrogen-deuterium exchange mass spectrometry, crosslinking
- MeSH terms
- Animals, Camelids, New World, Cattle, Humans, Mammals, Microscopy, Electron, Models, Molecular, Protein Binding, Mass Spectrometry, Receptors, Adrenergic, beta-2, Rats, G-Protein-Coupled Receptor Kinase 5, Molecular Dynamics Simulation
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