Analysis of human dopamine D3 receptor quaternary structure (original) (raw)

Marsango, Sara, Caltabiano, Gianluigi, Pou, Chantevy, Varela Liste, Maria Jose and Milligan, Graeme ORCID: https://orcid.org/0000-0002-6946-3519(2015) Analysis of human dopamine D3 receptor quaternary structure.Journal of Biological Chemistry, 290, pp. 15146-15162. (doi: 10.1074/jbc.M114.630681) (PMID:25931118) (PMCID:PMC4463457)

Abstract

The dopamine D3 receptor is a class A, rhodopsinlike G protein-coupled receptor that can form dimers and/or higher-order oligomers. However, the molecular basis for production of these complexes is not well defined. Using combinations of molecular modelling, site-directed mutagenesis and homogenous time-resolved FRET, the interfaces that allow dopamine D3 receptor monomers to interact were defined and used to describe likely quaternary arrangements of the receptor. These were then compared to published crystal structures of dimeric β1-adrenoceptor, μ-opioid and CXCR4 receptors. The data indicate important contributions of residues from within each of transmembrane domains I, II, IV, V, VI and VII, as well as the intracellular helix VIII, in the formation of D3-D3 receptor interfaces within homo-oligomers and are consistent with the D3 receptor adopting a β1-adrenoceptor-like quaternary arrangement. Specifically, results suggest that D3 protomers can interact with each other via at least two distinct interfaces: the first one comprising residues from transmembrane domains I and II along with those from helix VIII, and a second one involving transmembrane domains IV and V. Moreover, rather than existing only as distinct dimeric species the results are consistent with the D3 receptor also assuming a quaternary structure in which two transmembrane domain I-II-helix VIII dimers interact to form a 'rhombic' tetramer via an interface involving residues from transmembrane domains VI and VII. In addition, the results also provide insights into the potential contribution of molecules of cholesterol to the overall organization and potential stability of the D3 receptor, and possibly other, GPCR quaternary structures.

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Funder and Project Information

1

The organisational structure of class A GPCRs: Implications for pharmacology, function and therapeutic regulation

Graeme Milligan

MR/L023806/1

RI MOLECULAR CELL & SYSTEMS BIOLOGY

1

The organisational structure of class A GPCRs: implications for function and drug design

Graeme Milligan

G0900050

RI NEUROSCIENCE & PSYCHOLOGY

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