Abstract LB-288: Investigation on the interaction between human beta defensin type 3 (hBD-3) and ectodomain of EphA2 receptor using molecular dynamics simulation method

Abstract

Abstract Defensins are a family of cationic cysteine-rich small molecules. In general, human beta defensins (hBD) are produced by epithelial cells, and they are important to the human innate immune system. Experimental results showed that defensins can directly bind with receptors such as chemokine receptors and act through several mechanisms that may trigger antitumor immunity or facilitate the host's immune response (or evasion) and promote tumor progression. hBD type 3 (hBD-3) is newly discovered and is unique that it has a net charge density much higher than other family members, and has the ability to undergo oligomerization. On the other hand, EPH receptors and their corresponding ligands (ephrins) are membrane-bound proteins that require direct cell-cell interactions for the activation of the receptors. Eph-ephrin system plays a critical role in tumor and vascular functions during carcinogenesis. Once EPH receptor A2 (EphA2) is ligand-independent, it can over-express itself in many types of tumors, and behave like an oncogene. Besides, many studies suggested that mutations that affect EPH receptor function play a role in cancer initiation or progression. Therefore, the EphA2-ephrin5 system can be a novel target for the development of anti-tumorigenic and anti-angiogenic therapies, and understanding its interaction with other molecules is important to demystify the cancer mechanism. Both EphA2 ectodomain (ECD) and hBD-3 exist outside of the cell membrane. In order to find out the interaction mechanism of hBD-3 with EphA2 receptor, initially blind docking using Cluspro software was performed to predict all the possible binding sites between hBD-3 oligomer and EphA2 ECD in the free and bound forms. After that, all atom molecular dynamics CHARMM simulations were performed to find out the most probable binding interfaces between hBD-3 oligomer and EphA2 ECD. It was found that hBD-3 has multiple stable binding sites on the EphA2 ECD, and its binding on the ligand-binding domain (LBD) of EphA2 could influence the binding of ephrin5 with EphA2. Those suggest the hBD-3 could play a role in cancer initiation. Citation Format: Liqun Zhang. Investigation on the interaction between human beta defensin type 3 (hBD-3) and ectodomain of EphA2 receptor using molecular dynamics simulation method. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-288.