3AZA

Beta-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ) from Plasmodium falciparum in complex with NAS91-10

Summary for 3AZA

• Entry DOI: 10.2210/pdb3aza/pdb
• Related: 1Z6B 1ZHG 3AZ8 3AZ9 3AZB
• Descriptor: Beta-hydroxyacyl-ACP dehydratase, GLYCEROL, 8-(benzyloxy)-5-chloroquinoline, ... (4 entities in total)
• Functional Keywords: hot dog fold, fabz, beta-hydroxyacyl acyl carrier protein dehydratase, lyase, acyl carrier protein, lyase-inhibitor complex, lyase/inhibitor
• Biological source: Plasmodium falciparum
• Total number of polymer chains: 24
• Total formula weight: 412104.54

Authors

Maity, K.,Venkata, B.S.,Kapoor, N.,Surolia, N.,Surolia, A.,Suguna, K. (deposition date: 2011-05-21, release date: 2012-02-29, Last modification date: 2023-11-01)

Primary citation

Maity, K.,Venkata, B.S.,Kapoor, N.,Surolia, N.,Surolia, A.,Suguna, K.
Structural basis for the functional and inhibitory mechanisms of beta-hydroxyacyl-acyl carrier protein dehydratase (FabZ) of Plasmodium falciparum
J.Struct.Biol., 176:238-249, 2011

PubMed 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.

PubMed: 21843645
DOI: 10.1016/j.jsb.2011.07.018

Experimental method

X-RAY DIFFRACTION (2.7 Å)