Abstract
Rac1 is a small signaling protein, which belongs to the Rho subfamily of Ras superfamily. It is activated by binding GTP and inactivated by exchanging GDP for GTP. The ability of nucleotide exchange depends on guanine nucleotide exchange factors (GEFs) family proteins. T-lymphoma invasion and metastasis factor 1 (Tiam1) is a member of GEFs. Rac1 participates in multiple signaling pathways and regulates various cellular events by interacting with GEFs. Particularly, it is involved in the development and progression of various kinds of tumors. In this paper, we have studied the detailed interaction between Rac1 and Tiam1. Seven residues on Rac1 are predicted to be important for the interaction with Tiam1, i.e. E31, Y32, D38, N39, Y64, D65 and W56. All these residues are located on the switch 1 and 2 domains which are the interface between Rac1 and Tiam1, except W56. In addition, we analyzed how inhibitor NSC23766 interacts with Rac1. Our docking results show that NSC23766 binds to the same region as Tiam1. Several residues, i.e. F37, D38, N39, W56, Y64, L67, L70 and S71, contribute much to binding free energy. These findings are very useful for the structure-based design of inhibitors toward Rac1.
Highlights
Rac1, a member of Rho family GTPase, is found to involve in the development and progression of various kinds of tumors (Myant et al, 2013; Wang et al, 2015)
We have studied the detailed interaction between Rac1 and T-lymphoma invasion and metastasis factor 1 (Tiam1)
We found that Rac1 played an important role of tumor-promoting in the progression of esophageal squamous cell carcinoma (ESCC) and the expression of Rac1 was Theoretical Study on Rac1 positively related to cisplatin resistance in ESCC cells (Zeng et al, 2019)
Summary
A member of Rho family GTPase, is found to involve in the development and progression of various kinds of tumors (Myant et al, 2013; Wang et al, 2015). Similar to the other Rho GTPases, Rac could causes chemoresistance in various kinds of cancers It can be turned on and off as a molecular switch and transformed between inactive state with guanosine diphosphate (GDP) and active state with guanosine triphosphate (GTP) (Um et al, 2014; Cardama et al, 2017). During this process, the structure of Tiam was suggested to be adjusted for recognition and binding to Rac (Habets et al, 1994; Boissier and Huynh-Do, 2014). The crystal structure of Tiam1-Rac complex provides novel insights into developing therapeutic strategy to inhibit Rho GTPase activity and the associated downstream pathways (Akbar et al, 2006). This study provides valuable insights for the cancer treatment based on the inhibition of Rac
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
