7JV5

Cryo-EM structure of SKF-81297-bound dopamine receptor 1 in complex with Gs protein

Summary for 7JV5

• Entry DOI: 10.2210/pdb7jv5/pdb
• EMDB information: 22493
• Descriptor: D(1A) dopamine receptor, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (8 entities in total)
• Functional Keywords: dopamine receptor 2, gi protein, skf-81297, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 166797.07

Authors

Zhuang, Y.,Xu, P.,Mao, C.,Wang, L.,Krumm, B.,Zhou, X.E.,Huang, S.,Liu, H.,Cheng, X.,Huang, X.-P.,Sheng, D.-D.,Xu, T.,Liu, Y.-F.,Wang, Y.,Guo, J.,Jiang, Y.,Jiang, H.,Melcher, K.,Roth, B.L.,Zhang, Y.,Zhang, C.,Xu, H.E. (deposition date: 2020-08-20, release date: 2021-02-24, Last modification date: 2021-03-03)

Primary citation

Zhuang, Y.,Xu, P.,Mao, C.,Wang, L.,Krumm, B.,Zhou, X.E.,Huang, S.,Liu, H.,Cheng, X.,Huang, X.P.,Shen, D.D.,Xu, T.,Liu, Y.F.,Wang, Y.,Guo, J.,Jiang, Y.,Jiang, H.,Melcher, K.,Roth, B.L.,Zhang, Y.,Zhang, C.,Xu, H.E.
Structural insights into the human D1 and D2 dopamine receptor signaling complexes.
Cell, 184:931-942.e18, 2021

PubMed Abstract: The D1- and D2-dopamine receptors (D1R and D2R), which signal through G and G, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the central nervous system. D1R and D2R also represent the main therapeutic targets for Parkinson's disease, schizophrenia, and many other neuropsychiatric disorders, and insight into their signaling is essential for understanding both therapeutic and side effects of dopaminergic drugs. Here, we report four cryoelectron microscopy (cryo-EM) structures of D1R-G and D2R-G signaling complexes with selective and non-selective dopamine agonists, including two currently used anti-Parkinson's disease drugs, apomorphine and bromocriptine. These structures, together with mutagenesis studies, reveal the conserved binding mode of dopamine agonists, the unique pocket topology underlying ligand selectivity, the conformational changes in receptor activation, and potential structural determinants for G protein-coupling selectivity. These results provide both a molecular understanding of dopamine signaling and multiple structural templates for drug design targeting the dopaminergic system.

PubMed: 33571431
DOI: 10.1016/j.cell.2021.01.027

Experimental method

ELECTRON MICROSCOPY (3 Å)