Conformational transitions and allosteric modulation in a heteromeric glycine receptor.
Conformational transitions and allosteric modulation in a heteromeric glycine receptor.
复制标题
DOI：
10.1038/s41467-023-37106-7
复制
发表时间：
2023-03-13
影响因子：
16.6
通讯作者：
Chakrapani, Sudha
中科院分区：
文献类型：
--
作者：
Gibbs, Eric;Klemm, Emily;Seiferth, David;Kumar, Arvind;Ilca, Serban L.;Biggin, Philip C.;Chakrapani, Sudha
甘氨酸受体（GlyRs）在脊髓和脑干中提供抑制性神经元输入，对肌肉协调和感觉知觉至关重要。突触GlyRs是α和β亚基的异聚体。在这里，我们展示了全长斑马鱼α1βBGlyR在拮抗剂（士的宁）、激动剂（甘氨酸）或激动剂与正变构调节剂（甘氨酸/伊维菌素）存在下的冷冻电镜结构。每个结构都显示出不同程度的不对称的独特孔隙构象。分子动力学模拟发现结构处于封闭状态（士的宁）和脱敏状态（甘氨酸和甘氨酸/伊维菌素）。伊维菌素在所有五个界面上结合，但在β-α界面上以不同的结合姿势结合。亚基特异性特征足以在没有可信标记的情况下解决结构，并证实最近观察到的4α:1β化学计量学。我们还报告了细胞外和细胞内结构域的特征。总之，我们的研究结果显示了α1βGlyR的独特组成和构象特性，并为进一步研究这一生理上重要的通道提供了框架。甘氨酸受体（GlyR）是脊髓神经元突触后的重要组成部分。在这里，作者展示了异聚GlyR在拮抗剂、激动剂和具有正变构调节剂的激动剂存在下的低温电镜结构。
Glycine Receptors (GlyRs) provide inhibitory neuronal input in the spinal cord and brainstem, which is critical for muscle coordination and sensory perception. Synaptic GlyRs are a heteromeric assembly of α and β subunits. Here we present cryo-EM structures of full-length zebrafish α1βBGlyR in the presence of an antagonist (strychnine), agonist (glycine), or agonist with a positive allosteric modulator (glycine/ivermectin). Each structure shows a distinct pore conformation with varying degrees of asymmetry. Molecular dynamic simulations found the structures were in a closed (strychnine) and desensitized states (glycine and glycine/ivermectin). Ivermectin binds at all five interfaces, but in a distinct binding pose at the β-α interface. Subunit-specific features were sufficient to solve structures without a fiduciary marker and to confirm the 4α:1β stoichiometry recently observed. We also report features of the extracellular and intracellular domains. Together, our results show distinct compositional and conformational properties of α1βGlyR and provide a framework for further study of this physiologically important channel. Glycine receptors (GlyR) are a critical postsynaptic component of spinal neurons. Here, the auhtors present cryo-EM structures of a heteromeric GlyR in the presence of an antagonist, agonist and agonist with a positive allosteric modulator.
登录
查看更多内容
DOI：
10.1107/s2059798318009324
发表时间：
2018-09-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Klaholz BP;Moriarty NW;Poon BK;Sobolev OV;Terwilliger TC;Adams PD;Urzhumtsev A
通讯作者：
Urzhumtsev A
影响因子：
16.6
作者：
Gielen, Marc;Thomas, Philip;Smart, Trevor G.
通讯作者：
Smart, Trevor G.
影响因子：
48
作者：
Foley EDB;Kushwah MS;Young G;Kukura P
通讯作者：
Kukura P
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
64.8
作者：
GRENNINGLOH, G;RIENITZ, A;BETZ, H
通讯作者：
BETZ, H