Department of Biotechnology, National Institute of Technology, Warangal, Telangana, India.
Combinatorial Tumor Immunotherapy MRC, Chonnam National University Medical School, Hwasun-gun, Jeonnam, Republic of Korea.
PLoS One. 2023 Apr 6;18(4):e0283364. doi: 10.1371/journal.pone.0283364. eCollection 2023.
Estrogen-related receptor gamma (ERRγ), the latest member of the ERR family, does not have any known reported natural ligands. Although the crystal structures of the apo, agonist-bound, and inverse agonist-bound ligand-binding domain (LBD) of ERRγ have been solved previously, their dynamic behavior has not been studied. Hence, to explore the intrinsic dynamics of the apo and ligand-bound forms of ERRγ, we applied long-range molecular dynamics (MD) simulations to the crystal structures of the apo and ligand-bound forms of the LBD of ERRγ. Using the MD trajectories, we performed hydrogen bond and binding free energy analysis, which suggested that the agonist displayed more hydrogen bonds with ERRγ than the inverse agonist 4-OHT. However, the binding energy of 4-OHT was higher than that of the agonist GSK4716, indicating that hydrophobic interactions are crucial for the binding of the inverse agonist. From principal component analysis, we observed that the AF-2 helix conformation at the C-terminal domain was similar to the initial structures during simulations, indicating that the AF-2 helix conformation is crucial with respect to the agonist or inverse agonist for further functional activity of ERRγ. In addition, we performed residue network analysis to understand intramolecular signal transduction within the protein. The betweenness centrality suggested that few of the amino acids are important for residue signal transduction in apo and ligand-bound forms. The results from this study may assist in designing better therapeutic compounds against ERRγ associated diseases.
雌激素相关受体γ（ERRγ）是 ERR 家族的最新成员，目前尚无已知的天然配体。尽管先前已经解析了 ERRγ 的配体结合域（LBD）的无配体、激动剂结合和反向激动剂结合的晶体结构，但它们的动态行为尚未得到研究。因此，为了探索 ERRγ 的无配体和配体结合形式的固有动力学，我们应用长程分子动力学（MD）模拟了 ERRγ 的 LBD 的无配体和配体结合形式的晶体结构。使用 MD 轨迹，我们进行了氢键和结合自由能分析，结果表明激动剂与 ERRγ 形成的氢键比反向激动剂 4-OHT 更多。然而，4-OHT 的结合能高于激动剂 GSK4716，表明疏水相互作用对于反向激动剂的结合至关重要。从主成分分析中，我们观察到 C 末端结构域的 AF-2 螺旋构象与模拟过程中的初始结构相似，这表明 AF-2 螺旋构象对于 ERRγ 的进一步功能活性至关重要，无论是激动剂还是反向激动剂。此外，我们进行了残基网络分析，以了解蛋白质内的分子内信号转导。介数中心度表明，在无配体和配体结合形式中，只有少数氨基酸对于残基信号转导很重要。这项研究的结果可能有助于设计针对 ERRγ 相关疾病的更好的治疗化合物。
