Conformational and binding mode assessment of the human IL‐3 recognition by its alpha receptor

Protein-protein interactions (PPIs) are attractive targets as they are critical in a variety of biological processes and pathologies. As an illustration, the interleukin 3 (IL-3) and its α subunit receptor (IL-3Rα) are two proteins belonging to the cytokine or receptor βc family and are involved in several disorders like inflammatory diseases or hematological malignancies. This PPI exhibits a low binding affinity and a complex formed by a mutant form of IL-3 (superkine) and IL-3Rα have emerged from the literature, with an increase of the affinity. Therefore, in this study, we performed molecular dynamics simulations and binding energy calculation in order to evaluate protein dynamics and to characterize the main interactions between IL-3 and IL-3Rα, considering both wild-type and mutant. First, in the case of IL-3Rα/IL-3 wild-type complex, IL-3Rα can adopt three different conformations essentially driven by NTD domain, including the open and closed conformations, previously observed in crystal structures. Additionally, our results reveal a third conformation that has a distinct interaction profile that the others. Interestingly, these conformational changes are attenuated in IL-3Rα/IL-3 mutant complex. Then, we highlighted the contribution of different residues which interact principally with IL-3 or IL-3Rα conserved region. As for the mutated residue at position 135 of IL-3, other residues such as IL-3 E138, IL-3 D40, IL-3Rα Y279, IL-3Rα K235, or IL-3Rα R277 seem important for a low or a high binding affinity. Altogether these findings yield new information that could be exploited in a drug discovery process.