Identification of Oleanolic Acid as Allosteric Agonist of Integrin α(M) by Combination of In Silico Modeling and In Vitro Analysis

Oleanolic acid is a widely distributed natural product, which possesses promising antitumor, antiviral, antihyperlipidemic, and anti-inflammatory activities. A heterodimeric complex formed by integrin α(M) (CD11b) and integrin β(2) (CD18) is highly expressed on monocytes and macrophages. In the current study, we demonstrate that the I domain of α(M) (α(M)-I domain) might present a potential cellular target for oleanolic acid. In vitro data show that oleanolic acid induces clustering of α(M) on macrophages and reduces their non-directional migration. In accordance with experimental data, molecular docking revealed that oleanolic acid binds to the α(M)-I domain in its extended-open form, the dominant conformation found in α(M) clusters. Molecular dynamics simulation revealed that oleanolic acid can increase the flexibility of the α7 helix and promote its movement away from the N-terminus, indicating that oleanolic acid may facilitate the conversion of the α(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 α(M)-I domain in the open conformation partially through disturbance of the interactions between α1 and α7 helices. In summary, we demonstrate that oleanolic acid might function as an allosteric agonist inducing clustering of α(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.