Lim Herman D, Bartuzi Damian, Keen Alastair C, Rauffenbart Caroline, Glenn Jacqueline, Charlton Steven J, Lovera Silvia, Sands Zara A, Ates Ali, Wood Martyn, Canals Meritxell, Javitch Jonathan A, Carlsson Jens, Lane J Robert
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 399 Royal Parade, Parkville, VIC 3052, Australia.
Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala SE- 751 24, Sweden.
ACS Chem Neurosci. 2025 Jun 18;16(12):2295-2311. doi: 10.1021/acschemneuro.5c00105. Epub 2025 May 15.
Recently, the first small-molecule positive allosteric modulators (PAMs) of the dopamine D receptor (DR) were identified. The more potent PAM potentiated the effects of DR signaling in vitro and in an in vivo model predictive of anti-Parkinson's efficacy. We reveal, based on the results of our site-directed mutagenesis and molecular dynamics experiments, that this scaffold binds to a hitherto unexploited lipid-exposed extrahelical allosteric site in the DR that lies in a cleft toward the intracellular aspect of the DR defined by residues in transmembrane domains 1 and 7 and helix 8. By binding to this site, the PAM acts to potentiate the binding affinity of efficacious agonists, such as dopamine. Our simulations suggest that the PAM achieves this effect by stabilizing an active-like conformation of the receptor, similar to the G protein-bound state with TM5 and the tyrosine toggle switch playing the major role.
最近，多巴胺D受体（DR）的首个小分子正变构调节剂（PAM）被鉴定出来。效力更强的PAM在体外以及预测抗帕金森疗效的体内模型中增强了DR信号传导的作用。基于定点诱变和分子动力学实验的结果，我们发现，这种支架与DR中一个迄今未被开发利用的脂质暴露的螺旋外变构位点结合，该位点位于由跨膜结构域1和7中的残基以及螺旋8所界定的朝向DR细胞内一侧的裂隙中。通过与该位点结合，PAM起到增强有效激动剂（如多巴胺）结合亲和力的作用。我们的模拟表明，PAM通过稳定受体的类似活性的构象来实现这一效果，类似于G蛋白结合状态，其中TM5和酪氨酸切换开关起主要作用。
