Molecular interactions between fenoterol stereoisomers and derivatives and the β₂-adrenergic receptor binding site studied by docking and molecular dynamics simulations.
Molecular interactions between fenoterol stereoisomers and derivatives and the β₂-adrenergic receptor binding site studied by docking and molecular dynamics simulations.
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DOI：
10.1007/s00894-013-1981-y
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发表时间：
2013-11
影响因子：
2.2
通讯作者：
Jozwiak, Krzysztof
中科院分区：
文献类型：
--
作者：
Plazinska, Anita;Kolinski, Michal;Wainer, Irving W.;Jozwiak, Krzysztof
β2肾上腺素能受体（β2- ar）已成为研究G蛋白偶联受体的配体识别过程和激活机制的模型系统。本研究以非诺特罗及其衍生物（N = 94分子）的立体异构体作为分子探针，鉴定了β2-AR与结构相似的激动剂之间立体识别相互作用的差异。本研究旨在确定非诺特罗衍生物-β2-AR配合物的三维分子模型。利用人β2-AR T4溶菌酶融合蛋白与结合(S)-卡拉唑尔（PDB ID: 2RH1）的晶体结构和最近报道的β2-AR与结合的完全激动剂BI-167107 （PDB ID: 3P0G）的纳米体稳定活性状态的结构，建立了β2-AR的分子模型。对接过程使我们能够研究所测试配体识别结合位点的异同。激动剂分子占据相同的结合区，在TM III， TM V， TM VI和TM VII之间。我们在对接过程中发现的残基（Ser203, Ser207, Asp113, Lys305, Asn312, Tyr308, Asp192）在功能和生物物理研究中被实验证明对激动剂-受体相互作用非常重要。此外，确定并描述了附加空间，即矫形袋的延伸。此外，通过分子动力学模拟研究了配体（（R,R′）-和（S,S′）-非诺特罗）与β2-AR相互作用的分子机理。我们的研究为配体与最重要的GPCR成员之一的立体选择性相互作用提供了新的见解。这项研究也可能促进改进选择性药物的设计，可用于治疗、预防和控制心力衰竭症状。本文的在线版本（doi:10.1007/s00894-013-1981-y）包含补充材料，可供授权用户使用。
The β2 adrenergic receptor (β2-AR) has become a model system for studying the ligand recognition process and mechanism of the G protein coupled receptors activation. In the present study stereoisomers of fenoterol and some of its derivatives (N = 94 molecules) were used as molecular probes to identify differences in stereo-recognition interactions between β2-AR and structurally similar agonists. The present study aimed at determining the 3D molecular models of the fenoterol derivative-β2-AR complexes. Molecular models of β2-AR have been developed by using the crystal structure of the human β2-AR T4 lysozyme fusion protein with bound (S)-carazolol (PDB ID: 2RH1) and more recently reported structure of a nanobody-stabilized active state of the β2-AR with the bound full agonist BI-167107 (PDB ID: 3P0G). The docking procedure allowed us to study the similarities and differences in the recognition binding site(s) for tested ligands. The agonist molecules occupied the same binding region, between TM III, TM V, TM VI and TM VII. The residues identified by us during docking procedure (Ser203, Ser207, Asp113, Lys305, Asn312, Tyr308, Asp192) were experimentally indicated in functional and biophysical studies as being very important for the agonist-receptor interactions. Moreover, the additional space, an extension of the orthosteric pocket, was identified and described. Furthermore, the molecular dynamics simulations were used to study the molecular mechanism of interaction between ligands ((R,R’)- and (S,S’)-fenoterol) and β2-AR. Our research offers new insights into the ligand stereoselective interaction with one of the most important GPCR member. This study may also facilitate the design of improved selective medications, which can be used to treat, prevent and control heart failure symptoms. The online version of this article (doi:10.1007/s00894-013-1981-y) contains supplementary material, which is available to authorized users.
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影响因子：
3.5
作者：
Jozwiak, Krzysztof;Woo, Anthony Yiu-Ho;Tanga, Mary J.;Toll, Lawrence;Jimenez, Lucita;Kozocas, Joseph A.;Plazinska, Anita;Xiao, Rui-Ping;Wainer, Irving W.
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作者：
Oostenbrink, C;Villa, A;Van Gunsteren, WF
通讯作者：
Van Gunsteren, WF