Understanding the Binding Specificity of G‑Protein Coupled Receptors toward G‑Proteins and Arrestins: Application to the Dopamine Receptor Family

G-Protein coupled receptors (GPCRs)
are involved in a myriad of
pathways key for human physiology through the formation of complexes
with intracellular partners such as G-proteins and arrestins (Arrs).
However, the structural and dynamical determinants of these complexes
are still largely unknown. Herein, we developed a computational big-data
pipeline that enables the structural characterization of GPCR complexes
with no available structure. This pipeline was used to study a well-known group of catecholamine receptors,
the human dopamine receptor (DXR) family and its complexes, producing
novel insights into the physiological properties of these important
drug targets. A detailed description of the protein interfaces of
all members of the DXR family (D1R, D2R, D3R, D4R, and D5R) and the
corresponding protein interfaces of their binding partners (Arrs:
Arr2 and Arr3; G-proteins: Gi1, Gi2, Gi3, Go, Gob, Gq, Gslo, Gssh,
Gt2, and Gz) was generated. To produce reliable structures of the
DXR family in complex with either G-proteins or Arrs, we performed
homology modeling using as templates the structures of the β2-adrenergic
receptor (β2AR) bound to Gs, the rhodopsin bound to Gi, and
the recently acquired neurotensin receptor-1 (NTSR1) and muscarinic
2 receptor (M2R) bound to arrestin (Arr). Among others, the work demonstrated
that the three partner groups, Arrs and Gs- and Gi-proteins, are all
structurally and dynamically distinct. Additionally, it was revealed
the involvement of different structural motifs in G-protein selective
coupling between D1- and D2-like receptors. Having constructed and
analyzed 50 models involving DXR, this work represents an unprecedented
large-scale analysis of GPCR-intracellular partner interface determinants.
All data is available at www.moreiralab.com/resources/dxr.