Name
Title | ||
|---|---|---|
Understanding the binding specificity of G-protein coupled receptors towards G-proteins and Arrestins: application to the dopamine receptor family. |
Abstract | ||
|---|---|---|
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. |
Year | DOI | Venue |
|---|---|---|
2020 | 10.1021/acs.jcim.0c00371 | JOURNAL OF CHEMICAL INFORMATION AND MODELING |
DocType | Volume | Issue |
Journal | 60 | 8 |
ISSN | Citations | PageRank |
1549-9596 | 0 | 0.34 |
References | Authors | |
0 | 10 | |
Name | Order | Citations | PageRank |
|---|---|---|---|
| António José Preto | 1 | 0 | 0.34 |
| Carlos A V Barreto | 2 | 0 | 0.34 |
| Salete Baptista | 3 | 0 | 0.34 |
| Jose Almeida | 4 | 0 | 0.34 |
| Agostinho Lemos | 5 | 0 | 0.34 |
| André Melo | 6 | 0 | 0.68 |
| M. Natália D. S. Cordeiro | 7 | 14 | 6.58 |
| Zeynep Kurkcuoglu | 8 | 6 | 1.63 |
| Rita Melo | 9 | 0 | 0.34 |
| Irina S. Moreira | 10 | 38 | 4.98 |