9F34

Cryo-EM structure of Dopamine 3 receptor:Go complex bound to bitopic FOB02-04A - Conformation B

これはPDB形式変換不可エントリーです。

9F34 の概要

• エントリーDOI: 10.2210/pdb9f34/pdb
• 関連するPDBエントリー: 9F33
• EMDBエントリー: 50169
• 分子名称: Guanine nucleotide-binding protein G(o) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• 機能のキーワード: gpcr, complex, bitopic, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 190109.90

構造登録者

Arroyo-Urea, S.,Garcia-Nafria, J. (登録日: 2024-04-24, 公開日: 2024-09-18)

主引用文献

Arroyo-Urea, S.,Nazarova, A.L.,Carrion-Antoli, A.,Bonifazi, A.,Battiti, F.O.,Lam, J.H.,Newman, A.H.,Katritch, V.,Garcia-Nafria, J.
A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site.
Nat Commun, 15:7759-7759, 2024

PubMed Abstract: Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hDR:Gαβγ complex bound to the DR selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs.

PubMed: 39237617
DOI: 10.1038/s41467-024-51993-4

実験手法

ELECTRON MICROSCOPY (3.09 Å)