Structure and putative signaling mechanism of Protease activated receptor 2 (PAR2) – A promising target for breast cancer

• Multiple PAR2 model conformations were generated after molecular dynamics studies.
• The final PAR2 was selected based on the binding affinity studies with GB110.
• The putative ligands information was based on phylogenetic classification.
• Residues important for structural stability of PAR2 were identified.
• Binding modes of putative ligands was confirmed by molecular dynamics.

Experimental evidences have observed enhanced expression of protease activated receptor 2 (PAR2) in breast cancer consistently. However, it is not yet recognized as an important therapeutic target for breast cancer as the primary molecular mechanisms of its activation are not yet well-defined. Nevertheless, recent reports on the mechanism of GPCR activation and signaling have given new insights to GPCR functioning. In the light of these details, we attempted to understand PAR2 structure & function using molecular modeling techniques. In this work, we generated averaged representative stable models of PAR2, using protease activated receptor 1 (PAR1) as a template and selected conformation based on their binding affinity with PAR2 specific agonist, GB110. Further, the selected model was used for studying the binding affinity of putative ligands. The selected ligands were based on a recent publication on phylogenetic analysis of Class A rhodopsin family of GPCRs. This study reports putative ligands, their interacting residues, binding affinity and molecular dynamics simulation studies on PAR2-ligand complexes. The results reported from this study would be useful for researchers and academicians to investigate PAR2 function as its physiological role is still hypothetical. Further, this information may provide a novel therapeutic scheme to manage breast cancer.

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