title: Structure and putative signaling mechanism of Protease activated receptor 2 (PAR2) - a promising target for breast cancer.
abstract: 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.
authors.affiliation: Centre for Biotechnology and Bioinformatics (CBB), School of Life Sciences, Jawaharlal Nehru Institute of Advanced Studies (JNIAS), 6th Floor, Buddha Bhawan, M.G. Road, Secunderabad 500003, Andhra Pradesh, India. Electronic address: kavitakakarala@gmail.com.
authors.forename: Kavita Kumari
authors.initials: KK
authors.lastname: Kakarala
authors.affiliation: Centre for Biotechnology and Bioinformatics (CBB), School of Life Sciences, Jawaharlal Nehru Institute of Advanced Studies (JNIAS), 6th Floor, Buddha Bhawan, M.G. Road, Secunderabad 500003, Andhra Pradesh, India.
authors.forename: Kaiser
authors.initials: K
authors.lastname: Jamil
authors.affiliation: College of Pharmacy, Madras Medical College, E.V.R. Periyar Salai, Chennai 600003, India.
authors.forename: Vinod
authors.initials: V
authors.lastname: Devaraji
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D007555:Isoxazoles / Q000737:chemistry*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D009842:Oligopeptides / Q000737:chemistry*; D010802:Phylogeny; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D044464:Receptor, PAR-2 / Q000737:chemistry* / Q000235:genetics; D015398:Signal Transduction; D040681:Structural Homology, Protein
chemical_list: C553267:5-isoxazoyl-cyclohexylalanyl-isoleucyl-(3-(aminomethyl)phenyl)-(4-(aminomethyl)piperidin-1-yl)methanone; D000970:Antineoplastic Agents; D007555:Isoxazoles; D008024:Ligands; D009842:Oligopeptides; D044464:Receptor, PAR-2
keywords: Agonist; Antagonist; Binding affinity; Endogenous ligands; Homology modeling