Zeba Ayesha, Sekar Kanagaraj, Ganjiwale Anjali
Department of Life Sciences, Bangalore University, Bangalore, Karnataka 560056, India.
Laboratory for Structural Biology and Bio-computing, Computational and Data Sciences, Indian Institute of Science, Bangalore, Karnataka 560012, India.
Genomics Inform. 2023 Sep;21(3):e41. doi: 10.5808/gi.23035. Epub 2023 Sep 27.
The Dengue virus M protein is a 75 amino acid polypeptide with two helical transmembranes (TM). The TM domain oligomerizes to form an ion channel, facilitating viral release from the host cells. The M protein has a critical role in the virus entry and life cycle, making it a potent drug target. The oligomerization of the monomeric protein was studied using ab initio modeling and molecular dynamics (MD) simulation in an implicit membrane environment. The representative structures obtained showed pentamer as the most stable oligomeric state, resembling an ion channel. Glutamic acid, threonine, serine, tryptophan, alanine, isoleucine form the pore-lining residues of the pentameric channel, conferring an overall negative charge to the channel with approximate length of 51.9 Å. Residue interaction analysis (RIN) for M protein shows that Ala94, Leu95, Ser112, Glu124, and Phe155 are the central hub residues representing the physicochemical interactions between domains. The virtual screening with 165 different ion channel inhibitors from the ion channel library shows monovalent ion channel blockers, namely lumacaftor, glipizide, gliquidone, glisoxepide, and azelnidipine to be the inhibitors with high docking scores. Understanding the three-dimensional structure of M protein will help design therapeutics and vaccines for Dengue infection.
登革病毒M蛋白是一种由75个氨基酸组成的多肽，含有两个螺旋跨膜区（TM）。跨膜区寡聚化形成离子通道，促进病毒从宿主细胞中释放。M蛋白在病毒进入和生命周期中起关键作用，使其成为一个有效的药物靶点。在隐式膜环境中，使用从头建模和分子动力学（MD）模拟研究了单体蛋白的寡聚化。得到的代表性结构显示五聚体是最稳定的寡聚状态，类似于离子通道。谷氨酸、苏氨酸、丝氨酸、色氨酸、丙氨酸、异亮氨酸构成五聚体通道的孔内衬残基，赋予通道一个总负电荷，通道长度约为51.9 Å。M蛋白的残基相互作用分析（RIN）表明，Ala94、Leu95、Ser112、Glu124和Phe155是代表结构域之间物理化学相互作用的中心枢纽残基。对来自离子通道库的165种不同离子通道抑制剂进行虚拟筛选，结果显示单价离子通道阻滞剂，即鲁马卡托、格列吡嗪、格列喹酮、格列齐特和氨氯地平是对接分数较高的抑制剂。了解M蛋白的三维结构将有助于设计针对登革热感染的治疗药物和疫苗。
