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

• Published in: Journal of chemical information and modeling 2020-08, Vol.60 (8), p.3969-3984
• Main Authors: Preto, A. J, Barreto, Carlos A. V, Baptista, Salete J, Almeida, José Guilherme de, Lemos, Agostinho, Melo, André, Cordeiro, M. Nátalia D. S, Kurkcuoglu, Zeynep, Melo, Rita, Moreira, Irina S
• Format: Article
• Language: English
• Subjects: Arrestins; Binding; Catecholamine; Computational Biochemistry; Determinants; Dopamine; GTP-Binding Proteins; Homology; Humans; Proteins; Receptors; Receptors, Adrenergic, beta-2 - metabolism; Receptors, Dopamine; Receptors, G-Protein-Coupled - metabolism; Signal Transduction; Structural analysis
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.0c00371

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.