Mouse DPP4 (mDPP4) receptor is not a functional receptor for MERS-CoV while human DPP4 (hDPP4) is, despite the high similarities between hDPP4 and mDPP4 receptors. The variability of DPP4 receptors against MERS-CoV is not fully investigated, especially conformational and structural differences. Therefore, investigating the conformational differences of the DPP4 receptors can aid in developing new small animal models for MERS-CoV vaccines and antiviral agents evaluation. Here we used MD simulations and docking techniques to investigate these structural differences in DPP4 receptors. The results showed chimeric mouse mDPP4 (cmDPP4) has a similar compact conformation as wild-type hDPP4 based on the structural analysis. Interestingly, a single Thr288Ala mutation induced a relaxed conformation in chimeric 2 hDPP4 (c2hDPP4) and chimeric 2 mDPP4 (c2mDPP4); in addition to its significant effect on the DPP4 flexibility. The Thr288 residue is known for its critical function in MERS-CoV RBD interaction. Moreover, MERS-CoV RBD adopts a "standing" conformation when docked to hDPP4 and cmDPP4 in blade IV and V regions. In conclusion, the results could explain the functionality differences between mouse and human DPP4 receptors against MERS-CoV. However, further structural studies are needed to evaluate how DPP4 conformations affects MERS-CoV RBD binding and affinity. Communicated by Ramaswamy H. Sarma.