Picard Louis-Philippe, Orazietti Alexander, Tran Duy Phuoc, Tucs Andrejs, Hagimoto Sari, Qi Zhenzhou, Huang Shuya Kate, Tsuda Koji, Kitao Akio, Sljoka Adnan, Prosser R Scott
Department of Chemical and Physical Sciences, University of Toronto Mississauga (UTM), Mississauga, Ontario, Canada.
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Nat Chem Biol. 2025 Jan;21(1):71-79. doi: 10.1038/s41589-024-01682-6. Epub 2024 Jul 31.
The adenosine A receptor (AR) engages several G proteins, notably G and its cognate G protein. This coupling promiscuity is facilitated by a dynamic ensemble, revealed by F nuclear magnetic resonance imaging of AR and G protein. Two transmembrane helix 6 (TM6) activation states, formerly associated with partial and full agonism, accommodate the differing volumes of G and G. While nucleotide depletion biases TM7 toward a fully active state in AR-G, AR-G is characterized by a dynamic inactive/intermediate fraction. Molecular dynamics simulations reveal that the NPxxY motif, a highly conserved switch, establishes a unique configuration in the AR-G complex, failing to stabilize the helix-8 interface with G, and adoption of the active state. The resulting TM7 dynamics hamper G protein coupling, suggesting kinetic gating may be responsible for reduced efficacy in the noncognate G protein complex. Thus, dual TM6 activation states enable greater diversity of coupling partners while TM7 dynamics dictate coupling efficacy.
腺苷 A 受体（AR）与多种 G 蛋白相互作用，尤其是 Gαi 和其同源 G 蛋白。这种偶联的混杂性由 AR 和 G 蛋白的氟核磁共振成像揭示的动态集合所促进。两个跨膜螺旋 6（TM6）激活状态，以前与部分激动和完全激动相关，适应了 Gαi 和 Gαs 的不同体积。虽然核苷酸耗竭使 TM7 偏向 AR-Gαs 中的完全活跃状态，但 AR-Gαi 的特征是动态的非活性/中间部分。分子动力学模拟表明，高度保守的开关 NPxxY 基序在 AR-Gαi 复合物中建立了独特的构象，未能稳定与 Gαi 的螺旋 8 界面并采用活性状态。由此产生的 TM7 动力学阻碍了 G 蛋白偶联，表明动力学门控可能是导致非同源 G 蛋白复合物中效力降低的原因。因此，双重 TM6 激活状态使偶联伙伴具有更大的多样性，而 TM7 动力学决定了偶联效率。
