Structural insights into the subtype-selective antagonist binding to the M(2) muscarinic receptor.
Structural insights into the subtype-selective antagonist binding to the M(2) muscarinic receptor.
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DOI：
10.1038/s41589-018-0152-y
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发表时间：
2018-12
影响因子：
14.8
通讯作者：
Kobayashi T
中科院分区：
文献类型：
--
作者：
Suno R;Lee S;Maeda S;Yasuda S;Yamashita K;Hirata K;Horita S;Tawaramoto MS;Tsujimoto H;Murata T;Kinoshita M;Yamamoto M;Kobilka BK;Vaidehi N;Iwata S;Kobayashi T
人毒蕈碱受体M2是属于G蛋白偶联受体家族的毒蕈碱受体的五种亚型之一。毒蕈碱受体是多种神经退行性疾病的靶点。挑战在于设计针对五种毒蕈碱受体之一的亚型选择性配体。我们报告的高分辨率结构的热稳定突变M2受体结合亚型选择性拮抗剂AF-DX 384和非选择性拮抗剂NMS。M2中的热稳定突变S110 R是使用我们小组先前开发的理论策略预测的。M2受体的晶体结构和药理学性质的比较显示，S110 R突变体中的Arg模拟钠阳离子的稳定作用，已知钠阳离子变构稳定A类GPCR的非活性状态。分子动力学模拟显示，与M3受体相比，M2受体中配体-残基接触的收紧导致AF-DX 384的亚型选择性。
Human muscarinic receptor, M2 is one of the five subtypes of muscarinic receptors belonging to the family of G protein-coupled receptors. Muscarinic receptors are targets for multiple neurodegenerative diseases. The challenge has been designing subtype selective ligands against one of the five muscarinic receptors. We report high resolution structures of a thermostabilized mutant M2 receptor bound to a subtype selective antagonist AF-DX 384 and a non-selective antagonist NMS. The thermostabilizing mutation S110R in M2 was predicted using a theoretical strategy previously developed in our group. Comparison of the crystal structures and pharmacological properties of the M2 receptor shows that the Arg in the S110R mutant mimics the stabilizing role of the sodium cation, that is known to allosterically stabilize inactive state(s) of class A GPCRs. Molecular Dynamics simulations reveal that tightening of the ligand-residue contacts in M2 receptor compared to M3 receptor leads to subtype selectivity of AF-DX 384.
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影响因子：
4.1
作者：
BENNETT, CH
通讯作者：
BENNETT, CH
影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
3.6
作者：
Jakubik, Jan;El-Fakahany, Esam E.;Dolezal, Vladimir
通讯作者：
Dolezal, Vladimir
影响因子：
5
作者：
Kitaichi, K;Day, JC;Quirion, R
通讯作者：
Quirion, R
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH