期刊
FRONTIERS IN PHARMACOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.702529
关键词
oleanolic acid; integrin alpha(M); allosteric agonist; metadynamics; free energy profile
资金
- Project Complementary and Integrative Health Care by the German State of Baden-Wurttemberg [KIG BaWu]
- National Natural Science Foundation of China [82073735]
- Guangzhou Science and Technology Project [201904010203]
This study demonstrates that oleanolic acid may function as an allosteric agonist inducing clustering of alpha(M) on macrophages by shifting the balance from the closed to the extended-open conformation. The molecular target identified in this study holds potential for a purposeful use of oleanolic acid to modulate chronic inflammatory responses.
Oleanolic acid is a widely distributed natural product, which possesses promising antitumor, antiviral, antihyperlipidemic, and anti-inflammatory activities. A heterodimeric complex formed by integrin alpha(M) (CD11b) and integrin beta(2) (CD18) is highly expressed on monocytes and macrophages. In the current study, we demonstrate that the I domain of alpha(M) (alpha(M)-I domain) might present a potential cellular target for oleanolic acid. In vitro data show that oleanolic acid induces clustering of alpha(M) on macrophages and reduces their non-directional migration. In accordance with experimental data, molecular docking revealed that oleanolic acid binds to the alpha(M)-I domain in its extended-open form, the dominant conformation found in alpha(M) clusters. Molecular dynamics simulation revealed that oleanolic acid can increase the flexibility of the alpha 7 helix and promote its movement away from the N-terminus, indicating that oleanolic acid may facilitate the conversion of the alpha(M)-I domain from the extended-closed to the extended-open conformation. As demonstrated by metadynamics simulation, oleanolic acid can destabilize the local minimum of the alpha(M)-I domain in the open conformation partially through disturbance of the interactions between alpha 1 and alpha 7 helices. In summary, we demonstrate that oleanolic acid might function as an allosteric agonist inducing clustering of alpha(M) on macrophages by shifting the balance from the closed to the extended-open conformation. The molecular target identified in this study might hold potential for a purposeful use of oleanolic acid to modulate chronic inflammatory responses.
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