title: Structural and active site analysis of plasmepsins of Plasmodium falciparum: potential anti-malarial targets.
abstract: Comparative protein modeling, active site analysis and binding site specificity for the homologous series of plasmepsins (PM's), present in food vacuole of Plasmodium falciparum, are carried out. Four loops (L1, L2, L3 and L4), which show maximum structural deviations irrespective of type of inhibitor, have been identified. Comparison of the crystal structures of ligand complexes reveal that residues belonging to these loops have negligible coulomb and VDW interactions with the inhibitor but play major role in determining the openness of the binding cavity. The coulomb and VDW interactions between the PMII subsite pockets and inhibitors, which play a major role in determining the inhibition constants, are delineated. Besides small displacements, the catalytic residues D32 of PMII undergoes rotation around the Cgamma-Cbeta single bond to assist catalysis whereas side chain conformational deviations are not observed in D214 on plasmepsin activation. The mutant S79D of PMII (and the corresponding residues of PMI and PMIV) which helps in recognizing and cleaving substrates containing lysine at P1 position is surrounded by highly polar atmosphere stabilized by lysine. However, in PMIII significantly lower polar atmosphere around the mutant A78S/A78D is observed. Large buried side chain area of residues located at M15 and I289 of PMII (and corresponding residues of PMI and PMIV) corroborates well with increase in specificity constant for hydrophobic substrates.
authors.affiliation: Biology Division, Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors.forename: Rayavarapu
authors.initials: R
authors.lastname: Bhargavi
authors.forename: G Madhavi
authors.initials: GM
authors.lastname: Sastry
authors.forename: U Suryanarayana
authors.initials: US
authors.lastname: Murty
authors.forename: G Narahari
authors.initials: GN
authors.lastname: Sastry
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan / Q000737:chemistry; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry*; D001665:Binding Sites; D001703:Biophysics / Q000379:methods*; D020134:Catalytic Domain; D008024:Ligands; D008239:Lysine / Q000737:chemistry; D008958:Models, Molecular; D015233:Models, Statistical; D008969:Molecular Sequence Data; D009154:Mutation; D010436:Pepstatins / Q000737:chemistry; D010963:Plasmodium falciparum / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
chemical_list: D000953:Antigens, Protozoan; D000962:Antimalarials; D008024:Ligands; D010436:Pepstatins; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; D008239:Lysine; C031375:pepstatin