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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2020

Autores

Preto, AJ (Autor) Outra; Barreto, CAV (Autor) Outra; Baptista, SJ (Autor) Outra; de Almeida, JG (Autor) Outra; Lemos, A (Autor) Outra; Andre Melo (Autor) FCUP; Natalia N D S Cordeiro (Autor) FCUP; Kurkcuoglu, Z (Autor) Outra; Melo, R (Autor) Outra; Moreira, IS (Autor) Outra

Revista

Título: Journal of Chemical Information and Modeling

Vol. 60

Páginas: 3969-3984

ISSN: 1549-9596

Editora: American Chemical Society

Indexação

ISI Web of Knowledge - 5 Citações

Scopus - 7 Citações

Outras Informações

ID Authenticus: P-00S-MMP

DOI: 10.1021/acs.jcim.0c00371

Abstract (EN): 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 beta 2-adrenergic receptor (beta 2AR) 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 16