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Structure and Dynamics of G-Protein Coupled Receptors

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G Protein-Coupled Receptors - Modeling and Simulation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 796))

Abstract

G-protein coupled receptors (GPCRs) are seven helical transmembrane proteins that mediate cell-to-cell communication. They also form the largest superfamily of drug targets. Hence detailed studies of the three dimensional structure and dynamics are critical to understanding the functional role of GPCRs in signal transduction pathways, and for drug design. In this chapter we compare the features of the crystal structures of various biogenic amine receptors, such as β1 and β2 adrenergic receptors, dopamine D3 receptor, M2 and M3 muscarinic acetylcholine receptors. This analysis revealed that conserved residues are located facing the inside of the transmembrane domain in these GPCRs improving the efficiency of packing of these structures. The NMR structure of the chemokine receptor CXCR1 without any ligand bound, shows significant dynamics of the transmembrane domain, especially the helical kink angle on the transmembrane helix6. The activation mechanism of the β2-adrenergic receptor has been studied using multiscale computational methods. The results of these studies showed that the receptor without any ligand bound, samples conformations that resemble some of the structural characteristics of the active state of the receptor. Ligand binding stabilizes some of the conformations already sampled by the apo receptor. This was later observed in the NMR study of the dynamics of human β2-adrenergic receptor. The dynamic nature of GPCRs leads to a challenge in obtaining purified receptors for biophysical studies. Deriving thermostable mutants of GPCRs has been a successful strategy to reduce the conformational heterogeneity and stabilize the receptors. This has lead to several crystal structures of GPCRs. However, the cause of how these mutations lead to thermostability is not clear. Computational studies are beginning to shed some insight into the possible structural basis for the thermostability. Molecular Dynamics simulations studying the conformational ensemble of thermostable mutants have shown that the stability could arise from both enthalpic and entropic factors. There are regions of high stress in the wild type GPCR that gets relieved upon mutation conferring thermostability.

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Acknowledgements

We acknowledge the helpful discussions with Dr. Christopher Tate and Dr. Reinhard Grisshammer. We thank NIH-R01097261 for providing funding for our study on GPCR thermostable mutants.

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  1. Division of Immunology, Beckman Research Institute of the City of Hope, 1500, E. Duarte Road, Duarte, CA, 91010, USA

    Nagarajan Vaidehi, Supriyo Bhattacharya & Adrien B. Larsen

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  1. Nagarajan Vaidehi
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Correspondence to Nagarajan Vaidehi .

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  1. Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York,, New York, USA

    Marta Filizola

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Vaidehi, N., Bhattacharya, S., Larsen, A.B. (2014). Structure and Dynamics of G-Protein Coupled Receptors. In: Filizola, M. (eds) G Protein-Coupled Receptors - Modeling and Simulation. Advances in Experimental Medicine and Biology, vol 796. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7423-0_3

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