Crystal structure of dopamine D1 receptor in complex with G protein and a non-catechol agonist
| Autor: | Sebastian Kelm, Bingfa Sun, Inbar Fish, Matthew Ling-Hon Chu, Florence Lebon, Zara A. Sands, Martyn Wood, Dan Feng, Tong Sun Kobilka, Brian K. Kobilka, Silvia Lovera, Tom Ceska, Anne Valade |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Agonist Models Molecular medicine.drug_class G protein Protein Conformation Science General Physics and Astronomy In Vitro Techniques Molecular Dynamics Simulation Crystallography X-Ray Ligands Protein Engineering General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences 0302 clinical medicine Dopamine receptor D1 Receptor pharmacology In vivo Dopamine medicine Extracellular GTP-Binding Protein alpha Subunits Gs Humans Receptor Protein Structure Quaternary X-ray crystallography Multidisciplinary Binding Sites Chemistry Receptors Dopamine D1 General Chemistry Ligand (biochemistry) Recombinant Proteins 030104 developmental biology Biophysics Structural biology 030217 neurology & neurosurgery medicine.drug Protein Binding |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-9 (2021) |
| ISSN: | 2041-1723 |
| Popis: | Dopamine D1 receptor (D1R) is an important drug target implicated in many psychiatric and neurological disorders. Selective agonism of D1R are sought to be the therapeutic strategy for these disorders. Most selective D1R agonists share a dopamine-like catechol moiety in their molecular structure, and their therapeutic potential is therefore limited by poor pharmacological properties in vivo. Recently, a class of non-catechol D1R selective agonists with a distinct scaffold and pharmacological properties were reported. Here, we report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a non-catechol agonist Compound 1 at 3.8 Å resolution. The structure reveals the ligand bound to D1R in an extended conformation, spanning from the orthosteric site to extracellular loop 2 (ECL2). Structural analysis reveals that the unique features of D1R ligand binding pocket explains the remarkable selectivity of this scaffold for D1R over other aminergic receptors, and sheds light on the mechanism for D1R activation by the non-catechol agonist. Recently, a class of non-catechol Dopamine D1 receptor (D1R) selective agonists with novel scaffold and improved pharmacological properties were reported. Here, authors report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a non-catechol agonist Compound 1 which explains the selectivity of this scaffold for D1R over other aminergic receptors and the mechanism of activating D1R. |
| Databáze: | OpenAIRE |
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