2GLV

Crystal structure of (3R)-Hydroxyacyl-Acyl Carrier Protein Dehydratase(FabZ) mutant(Y100A) from Helicobacter pylori

Summary for 2GLV

• Entry DOI: 10.2210/pdb2glv/pdb
• Related: 2GLL 2glm 2glp
• Descriptor: (3R)-hydroxymyristoyl-acyl carrier protein dehydratase, CHLORIDE ION (3 entities in total)
• Functional Keywords: fabz mutant, lyase
• Biological source: Helicobacter pylori
• Cellular location: Cytoplasm : Q5G940
• Total number of polymer chains: 12
• Total formula weight: 234660.14

Authors

Zhang, L.,Liu, W.,Shen, X.,Jiang, H. (deposition date: 2006-04-05, release date: 2007-03-13, Last modification date: 2023-10-25)

Primary citation

Zhang, L.,Liu, W.,Hu, T.,Du, L.,Luo, C.,Chen, K.,Shen, X.,Jiang, H.
Structural basis for catalytic and inhibitory mechanisms of beta-hydroxyacyl-acyl carrier protein dehydratase (FabZ).
J.Biol.Chem., 283:5370-5379, 2008

PubMed Abstract: beta-Hydroxyacyl-acyl carrier protein dehydratase (FabZ) is an important enzyme for the elongation cycles of both saturated and unsaturated fatty acids biosyntheses in the type II fatty acid biosynthesis system (FAS II) pathway. FabZ has been an essential target for the discovery of compounds effective against pathogenic microbes. In this work, to characterize the catalytic and inhibitory mechanisms of FabZ, the crystal structures of the FabZ of Helicobacter pylori (HpFabZ) and its complexes with two newly discovered inhibitors have been solved. Different from the structures of other bacterial FabZs, HpFabZ contains an extra short two-turn alpha-helix (alpha4) between alpha3 and beta3, which plays an important role in shaping the substrate-binding tunnel. Residue Tyr-100 at the entrance of the tunnel adopts either an open or closed conformation in the crystal structure. The crystal structural characterization, the binding affinity determination, and the enzymatic activity assay of the HpFabZ mutant (Y100A) confirm the importance of Tyr-100 in catalytic activity and substrate binding. Residue Phe-83 at the exit tunnel was also refined in two alternative conformations, leading the tunnel to form an L-shape and U-shape. All these data thus contributed much to understanding the catalytic mechanism of HpFabZ. In addition, the co-crystal structures of HpFabZ with its inhibitors have suggested that the enzymatic activity of HpFabZ could be inhibited either by occupying the entrance of the tunnel or plugging the tunnel to prevent the substrate from accessing the active site. Our study has provided some insights into the catalytic and inhibitory mechanisms of FabZ, thus facilitating antibacterial agent development.

PubMed: 18093984
DOI: 10.1074/jbc.M705566200

Experimental method

X-RAY DIFFRACTION (2.5 Å)