De novo modeling and structural characterization of IL9-IL9 receptor complex: a potential drug target for hematopoietic stem cell therapy

Abstract

Hematopoietic stem cell therapy can control disease-related complications in neonatal disorders of newborns. The IL9-IL9R complex is one of the most multifunctional cytokine complexes that promote proliferation and differentiation of hematopoietic progenitors. However, the structure of this complex has not been determined yet. The present work demonstrates a de novo computational method for rational protein designing to recapitulate the structural relationship among IL9: IL9R complex. We employed a strategy to design mimics of IL-9 that binds to IL-9Rα by molecular modeling and protein–protein docking approach. For the simulation purpose, each complex was simulated under discrete setups (i) Apo: IL9; (ii) Apo: IL9R; (iii) IL9: IL9R complex. A 50 ns MD simulation was performed for Apo proteins, and a 35 ns simulation was run for the docked complex with a total number of 2027 of frames, both using 0.02 fs time step. The results revealed that the docked complex was stable, binding with a higher affinity at the site of the immunoglobin (Ig) domain, and elicit downstream cell signaling. Ig domain, fibronectin type III domain, and WSXWS motif were present in the modeled complex structure, which represents a highly promising target. The simulated complex reached an equilibrium state and indicate that THR52, SER53, CYS54, CYS56, GLU71, GLN75, ASN78, THR79, MET81, GLU110, PRO112, ASN114, GLN115 and ALA118 residues of IL9 structure were involved with THR53, PHE54, ALA70, PRO71, GLY74, GLU130, VAL132, SER133, LEU134, VAL135, ASP136, PRO137, GLU138, TYR241 and THR242 residues of IL9R structure. The data presented herein provide important insights into the molecular structure of IL9-IL9R complex and offers a promising target complex for drug design studies in the field of hematopoietic stem cell therapy.