GPCR large-amplitude dynamics by (19)F-NMR of aprepitant bound to the neurokinin 1 receptor.
GPCR large-amplitude dynamics by (19)F-NMR of aprepitant bound to the neurokinin 1 receptor.
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阿瑞匹坦与神经激肽 1 受体结合的 GPCR 大振幅动力学，通过 19 F-NMR 得到
DOI：
10.1073/pnas.2122682119
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发表时间：
2022-04-12
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
通过X射线晶体学或冷冻电子显微镜确定的G蛋白偶联受体（GPCR）结构包括28种受体，可以比较与激动剂和拮抗剂的复合物。在所有这些比较中，表示正构配体结合沟的大小的原子间距离相差小于2.9 μ m。在这份报告中，NK 1 R结合药物分子阿瑞匹坦的19 F-NMR观察表明，正构结合沟经历了幅度为6至8 μ m的瞬态波动。我们建议，这种大幅度的可塑性，使一个多步骤的功能配体的选择与可变的功效。这些见解结构动力学也提供了一个观察，衍射晶体获得的GPCR复合物只有很少的配体结合到受体的理由。基于X射线晶体学和冷冻电子显微镜结构测定的G蛋白偶联受体（GPCR）复合物与激动剂和拮抗剂的比较显示，在0.3至2.9 μ m的范围内，正构配体结合沟的宽度存在差异。在这里，我们表明，有瞬态结构波动的振幅高达至少6 Ω。这些实验是用神经激肽1受体（NK 1 R）进行的，NK 1 R是一种A类GPCR，与炎症、疼痛和癌症有关。我们使用阿瑞匹坦的19 F-NMR观察，阿瑞匹坦是一种批准的药物，靶向NK 1 R，用于治疗化疗引起的恶心和呕吐。阿瑞匹坦包括用单键连接到分子核心的双-三氟甲基-苯基环; 19 F-NMR揭示了该环围绕该键的180°翻转运动。在19 F-NMR数据中出现的图片中，GPCR跨膜螺旋在脂质双层中进行大规模的浮动运动。的功能的含义是广泛的混杂的初始配体结合，主要由配体的大小和形状，随后的选择通过独特的相互作用之间的原子团的配体和GPCR内的结合槽。这第二步确保了GPCR靶向药物记录的广泛的不同功效。NK 1 R数据还为以下观察结果提供了理论基础：衍射GPCR晶体是从批准的药物和与受体结合的先导化合物的库中获得的仅具有非常少的配体的复合物。
G protein-coupled receptor (GPCR) structures determined by X-ray crystallography or cryo-electron microscopy include 28 receptors for which complexes with agonists and antagonists can be compared. In all these comparisons, an interatomic distance representing the size of the orthosteric ligand binding groove differs by less than 2.9 Å. In this report, 19F-NMR observations of the NK1R-bound drug molecule aprepitant show that the orthosteric binding groove undergoes transient fluctuations with amplitudes 6 to 8 Å. We propose that this large-amplitude plasticity enables a multistep selection of functional ligands with variable efficacies. These insights into structural dynamics also provide a rationale for the observation that diffracting crystals are obtained for GPCR complexes with only few of the ligands that bind to the receptors. Comparisons of G protein-coupled receptor (GPCR) complexes with agonists and antagonists based on X-ray crystallography and cryo-electron microscopy structure determinations show differences in the width of the orthosteric ligand binding groove over the range from 0.3 to 2.9 Å. Here, we show that there are transient structure fluctuations with amplitudes up to at least 6 Å. The experiments were performed with the neurokinin 1 receptor (NK1R), a GPCR of class A that is involved in inflammation, pain, and cancer. We used 19F-NMR observation of aprepitant, which is an approved drug that targets NK1R for the treatment of chemotherapy-induced nausea and vomiting. Aprepitant includes a bis-trifluoromethyl-phenyl ring attached with a single bond to the core of the molecule; 19F-NMR revealed 180° flipping motions of this ring about this bond. In the picture emerging from the 19F-NMR data, the GPCR transmembrane helices undergo large-scale floating motions in the lipid bilayer. The functional implication is of extensive promiscuity of initial ligand binding, primarily determined by size and shape of the ligand, with subsequent selection by unique interactions between atom groups of the ligand and the GPCR within the binding groove. This second step ensures the wide range of different efficacies documented for GPCR-targeting drugs. The NK1R data also provide a rationale for the observation that diffracting GPCR crystals are obtained for complexes with only very few of the ligands from libraries of approved drugs and lead compounds that bind to the receptors.
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影响因子：
64.5
作者：
Huang, Shuya Kate;Pandey, Aditya;Duy Phuoc Tran;Villanueva, Nicolas L.;Kitao, Akio;Sunahara, Roger K.;Sljoka, Adnan;Prosser, R. Scott
通讯作者：
Prosser, R. Scott
DOI：
10.1126/science.1215802
发表时间：
2012-03-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Liu JJ;Horst R;Katritch V;Stevens RC;Wüthrich K
通讯作者：
Wüthrich K
影响因子：
2.7
作者：
Liu, Dongsheng;Wuthrich, Kurt
通讯作者：
Wuthrich, Kurt
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
影响因子：
4.4
作者：
FORSEN, S;HOFFMAN, RA
通讯作者：
HOFFMAN, RA