Fungal alkaloid malbrancheamide reorients the lipid binding domain of GRK5

Abstract

G protein-coupled receptors (GPCRs) are the largest group of receptors involved in various types of signaling. GPCR signaling is regulated via receptor phosphorylation by G protein-coupled receptor kinases 5 (GRK5). Calmodulin (CaM), a universal Ca²⁺ sensor, inhibits receptor phosphorylation by binding to GRK5. However, the inhibitor malbrancheamide (MBC), which binds at CaM C-lobe, allows for receptor phosphorylation. To understand the phosphorylation mechanism by GRK5, we carried out a MD simulation of the CaM/GRK5 complex in the presence and absence of the MBC inhibitor. The lipid binding domain (LBD) of GRK5 adopted different positions in the presence and absence of inhibitor. Furthermore, the inhibitor MBC restricted the movement of the N-lobe tether (NLT) loop, probably blocking the autophosphorylation of GRK5.

Communicated by Ramaswamy H. Sarma

Keywords:

• Calmodulin
• G protein-coupled receptors
• GRK5
• malbrancheamide
• MD simulations

Data availability statement

The simulation trajectories used in this study are available from the corresponding author upon reasonable request.

Acknowledgments

MD simulations were performed on the IIT Delhi HPC facility. (https://supercomputing.iitd.ac.in/). The author thanks Dr. Manish Agarwal, IIT Delhi, for the discussion during the manuscript preparation.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Department of Biotechnology, Ministry of Science and Technology, Govt. of India.