Depart of Pharmacy, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
Depart of Pharmacy, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
Biochim Biophys Acta Gen Subj. 2021 Jul;1865(7):129907. doi: 10.1016/j.bbagen.2021.129907. Epub 2021 Apr 9.
Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are two important pro-inflammatory cytokines of the interleukin-6 (IL-6) family. The two cytokines mediated signaling was recently found to be closely associated with cancer and chronic inflammation, which represent promising therapeutic targets for the treatment of many solid tumors and inflammatory disease. As the most closely related members, cross-reactivity of them may result in undesired activation of off-target cells, leading to toxicity or lack of efficacy of the therapeutic effects. However, the mechanism of the cross-reactivity of OSM and LIF is not well understood.
In this work, protein-protein docking, molecular dynamics (MD) simulations with explicit solvent and post endpoints binding free energy (BFE) analysis were carried out to further understand the structural and energetic principles of interactions between the two cytokines and the shared receptor LIFR.
For the first time, the simulation given a computational model of OSM-LIFR interaction, and provided significant insights into the mechanism of OSM and LIF cross-react with LIFR. The identified common features shared by OSM and LIF bind to LIFR involving 10 "conserved" residues (90% similarity) distributed at the binding site III comprised of AB loop, BC loop and D helix. In addition, 11 shared residues were identified in LIFR contribute 77.85% and 84.63% energies for OSM and LIF binding, which play a critical role in the formation of the two cytokine-receptor complexes. Moreover, the "nonconserved" residues at the same position of cytokines such as Asp41 in OSM and Pro51 in LIF as well as the three residues (Glu338, Asn201 and Glu260) in LIFR were also discovered.
These important information may facilitate the rational design of novel chemical or biological agents with less toxicity and improved efficacy.
抑瘤素 M（OSM）和白血病抑制因子（LIF）是白细胞介素 6（IL-6）家族中的两种重要促炎细胞因子。最近发现，这两种细胞因子的信号转导与癌症和慢性炎症密切相关，它们是治疗许多实体瘤和炎症性疾病的有前途的治疗靶点。作为最密切相关的成员，它们的交叉反应可能导致对靶细胞的不期望激活，从而导致治疗效果的毒性或缺乏疗效。然而，OSM 和 LIF 交叉反应的机制尚不清楚。
在这项工作中，进行了蛋白质-蛋白质对接、含显式溶剂的分子动力学（MD）模拟和后末端结合自由能（BFE）分析，以进一步了解两种细胞因子与共享受体 LIFR 之间相互作用的结构和能量原理。
首次模拟给出了 OSM-LIFR 相互作用的计算模型，并为 OSM 和 LIF 与 LIFR 交叉反应的机制提供了重要的见解。确定了 OSM 和 LIF 与 LIFR 结合所共有的 10 个“保守”残基（90%相似性），分布在由 AB 环、BC 环和 D 螺旋组成的结合位点 III 中。此外，在 LIFR 中发现了 11 个共有残基，它们对 OSM 和 LIF 的结合贡献了 77.85%和 84.63%的能量，在两个细胞因子-受体复合物的形成中起着关键作用。此外，还发现了细胞因子中相同位置的“非保守”残基，如 OSM 中的 Asp41 和 LIF 中的 Pro51 以及 LIFR 中的三个残基（Glu338、Asn201 和 Glu260）。
这些重要信息可能有助于设计毒性更小、疗效更好的新型化学或生物制剂。
