To probe the activation mechanism of the Delta opioid receptor by an agonist ADL5859 started from inactive conformation using molecular dynamic simulations
To probe the activation mechanism of the Delta opioid receptor by an agonist ADL5859 started from inactive conformation using molecular dynamic simulations
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DOI：
10.1080/07391102.2022.2107074
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发表时间：
2022-08
影响因子：
4.4
通讯作者：
Emily Dean;Prof Vikas Kumar;Ashleigh McConnell;Iohana B Pagnoncelli;Chun Wu
中科院分区：
文献类型：
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作者：
Emily Dean;Prof Vikas Kumar;Ashleigh McConnell;Iohana B Pagnoncelli;Chun Wu
摘要 δ-阿片受体（DOR）是疼痛管理的关键药物靶点。尽管最近已经解决了具有激动剂和拮抗剂的 DOR 的高分辨率晶体结构，但其激活机制仍然难以捉摸。在本研究中，将 DOR 激动剂 ADL5859 与失活的 DOR 对接，并进行多微秒分子动力学 (MD) 模拟来探讨激活机制。虽然具有晶体配体（即拮抗剂纳曲吲哚）的受体在所有三个独立模拟中都保持非活性构象，但具有 ADL5859 的受体在六个独立模拟中的三个中采用活性构象。主要构象差异位于跨膜 (TM) 5 和 6 以及细胞内环 3。与纳曲吲哚相比，ADL5859 表现出较高的构象灵活性以及与传输开关的强相互作用。通过常规分子开关分析和成对距离分析，鉴定了参与激活途径的假定关键残基（W274、D95、V267、L139、V263、M142、T260、R146、R258等），为实验诱变研究提供了一个简短的列表。这些见解将促进针对 DOR 的治疗药物的进一步开发。拉马斯瓦米·萨尔马 (Ramaswamy H. Sarma) 通讯
Abstract The δ-opioid receptor (DOR) is a critical pharmaceutical target for pain management. Although the high-resolution crystal structures of the DOR with both agonist and antagonist have recently been solved, the activation mechanism remains to be elusive. In this study, a DOR agonist ADL5859 was docked to the inactive DOR and multiple microsecond molecular dynamic (MD) simulations were conducted to probe the activation mechanism. While the receptor with the crystal ligand (i.e. antagonist naltrindole) maintained the inactive conformation in all three independent simulations, the receptor with ADL5859 was adopting toward the active conformation in three out of six independent simulations. Major conformational differences were located on transmembrane (TM) 5 and 6, as well as intracellular loop 3. Compared to naltrindole, ADL5859 exhibited high conformational flexibility and strong interaction with the transmission switch. The putative key residues (W274, D95, V267, L139, V263, M142, T260, R146, R258 and others) involving in the activation pathway were identified through the conventional molecular switch analysis and a pairwise distance analysis, which provides a short list for experimental mutagenesis study. These insights will facilitate further development of therapeutic agents targeting the DOR. Communicated by Ramaswamy H. Sarma