title: Structural basis for the functional and inhibitory mechanisms of β-hydroxyacyl-acyl carrier protein dehydratase (FabZ) of Plasmodium falciparum.
abstract: The β-hydroxyacyl-acyl carrier protein dehydratase of Plasmodium falciparum (PfFabZ) catalyzes the third and important reaction of the fatty acid elongation cycle. The crystal structure of PfFabZ is available in hexameric (active) and dimeric (inactive) forms. However, PfFabZ has not been crystallized with any bound inhibitors until now. We have designed a new condition to crystallize PfFabZ with its inhibitors bound in the active site, and determined the crystal structures of four of these complexes. This is the first report on any FabZ enzyme with active site inhibitors that interact directly with the catalytic residues. Inhibitor binding not only stabilized the substrate binding loop but also revealed that the substrate binding tunnel has an overall shape of "U". In the crystal structures, residue Phe169 located in the middle of the tunnel was found to be in two different conformations, open and closed. Thus, Phe169, merely by changing its side chain conformation, appears to be controlling the length of the tunnel to make it suitable for accommodating longer substrates. The volume of the substrate binding tunnel is determined by the sequence as well as by the conformation of the substrate binding loop region and varies between organisms for accommodating fatty acids of different chain lengths. This report on the crystal structures of the complexes of PfFabZ provides the structural basis of the inhibitory mechanism of the enzyme that could be used to improve the potency of inhibitors against an important component of fatty acid synthesis common to many infectious organisms.
authors.affiliation: Molecular Biophysics Unit, Indian Institute of Science, Bangalore - 560 012, India.
authors.forename: Koustav
authors.initials: K
authors.lastname: Maity
authors.forename: Bharat Somireddy
authors.initials: BS
authors.lastname: Venkata
authors.forename: Neha
authors.initials: N
authors.lastname: Kapoor
authors.forename: Namita
authors.initials: N
authors.lastname: Surolia
authors.forename: Avadhesha
authors.initials: A
authors.lastname: Surolia
authors.forename: Kaza
authors.initials: K
authors.lastname: Suguna
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000962:Antimalarials / Q000737:chemistry; D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004746:Enoyl-CoA Hydratase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000201:enzymology*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D013499:Surface Properties
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D004746:Enoyl-CoA Hydratase