title: In silico characterization of atypical kinase PFD0975w from Plasmodium kinome: a suitable target for drug discovery.
abstract: RIO-2 kinase is known to regulate ribosome biogenesis and other cell cycle events. The 3D model of ATP bound and an unbound form of PFD0975w was generated using AfRIO-2 crystal structure 1TQI, 1ZAO as template employing Modeller9v7 program. Structural characterization identified N-terminal winged helix domain (1-84), C-terminal kinase domain (148-275), and presence of other critical residues known for ATP binding and kinase activity. Using Q-site and pocket finder, a number of well-defined substrate (peptide) binding regions were identified in the catalytic core of the protein. The peptide binding regions were further validated by molecular modeling a non-specific polyalanine peptide and a sequence-specific peptide2 into these sites to generate a stable PFD0975w/peptide complexes. Peptide fits well into identified pocket on PFD0975w and makes extensive interaction with the protein residues. These newly identified peptide binding sites potentially give opportunity to design a specific inhibitor against PFD0975w. There are subtle but significant differences between Plasmodium falciparum and human RIO-2 to exploit PFD0975w for drug development. In conclusion, our finding will let us to design effective chemotherapy against malaria parasite exploiting PFD0975w as a drug target.
authors.affiliation: Department of Biotechnology, Malaria Research Group, Indian Institute of Technology-Guwahati, Guwahati-781039, Assam, India. vtrivedi@iitg.ernet.in
authors.forename: Vishal
authors.initials: V
authors.lastname: Trivedi
authors.forename: Swagata
authors.initials: S
authors.lastname: Nag
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000962:Antimalarials / Q000737:chemistry*; D001665:Binding Sites; D055808:Drug Discovery; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D008969:Molecular Sequence Data; D010770:Phosphotransferases / Q000737:chemistry* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000737:chemistry / Q000201:enzymology*; D012270:Ribosomes / Q000201:enzymology; D016415:Sequence Alignment
chemical_list: D000962:Antimalarials; D000255:Adenosine Triphosphate; D010770:Phosphotransferases