Proteins Containing Leucine Rich Repeats as Potential Targets for Plasmodium knowlesi
In parasitic organisms, proteins containing repeats especially leucine-rich repeats (LRRs) play an important role in invasion and immune evasion. LRR containing domains are responsible for different types of protein-protein interactions. We have taken advantage of available computational methods to structurally and functionally analyse, and to facilitate multifaceted insights into Plasmodium knowlesi leucine-rich repeats containing proteins. We have identified thirteen leucine-rich repeat (LRR) containing protein sequences in P. knowlesi. The sequential and structural similarities of these repeats containing proteins were checked against their recently emerged human host. Among the thirteen identified leucine-rich repeats containing protein sequences of P. knowlesi, only two (B3L5R8 and B3L378) were found to be unique and thus, selected for in-depth study. The pathogenic and virulence properties of B3L5R8 and B3L378 proteins were studied along with their dissimilarity with the human host proteins, suggesting their important role in disease establishment. These two proteins may be used as a novel targets for the development of drugs and vaccines against the disease.
The three dimensional structures of these proteins were modeled using threading approach. Ramachandran analysis was used to validate the modeled structures. Structurally, LRR domains of B3L5R8 and B3L378 consist of a structural motif that forms α/β horseshoe shape fold with the concave face consisting of parallel β-strands and the convex face representing helices. LRR domain in B3L5R8 and B3L378 proteins contains 12 and 17 coiled sub-structures respectively. The active site of the proteins is predicted to study their functionality. The modeled structure of B3L5R8 displays three functional sites which interact with different ligands: 2S8, peptides and nucleic acids. While the predicted structure of B3L378 interact with GAL, nucleic acid, RX8 and 2Z7XA03 at their four functional sites. The key amino acid residues involved in interaction with their respective ligand at the different active site of B3L5R8 and B3L378 proteins are responsible for stability of diverse ligands. These compounds along with the interacting amino acids may serve as a representative for designing novel inhibitors.