2go4

From Proteopedia

proteopedia linkproteopedia link

spinqualitylabelsall models 2go4, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of Aquifex aeolicus LpxC complexed with TU-514

Overview

The metal-dependent deacetylase LpxC catalyzes the first committed step of, lipid A biosynthesis in Gram-negative bacteria. Accordingly, LpxC is an, attractive target for the development of inhibitors that may serve as, potential new antibiotics for the treatment of Gram-negative bacterial, infections. Here, we report the 2.7 A resolution X-ray crystal structure, of LpxC complexed with the substrate analogue inhibitor TU-514 and the 2.0, A resolution structure of LpxC complexed with imidazole. The X-ray crystal, structure of LpxC complexed with TU-514 allows for a detailed examination, of the coordination geometry of the catalytic zinc ion and other, enzyme-inhibitor interactions in the active site. The hydroxamate group of, TU-514 forms a bidentate chelate complex with the zinc ion and makes, hydrogen bond interactions with conserved active site residues E78, H265, and T191. The inhibitor C-4 hydroxyl group makes direct hydrogen bond, interactions with E197 and H58. Finally, the C-3 myristate moiety of the, inhibitor binds in the hydrophobic tunnel of the active site. These, intermolecular interactions provide a foundation for understanding, structural aspects of enzyme-substrate and enzyme-inhibitor affinity., Comparison of the TU-514 complex with cacodylate and imidazole complexes, suggests a possible substrate diphosphate binding site and highlights, residues that may stabilize the tetrahedral intermediate and its flanking, transition states in catalysis. Evidence of a catalytic zinc ion in the, native zinc enzyme coordinated by H79, H238, D242, and two water molecules, with square pyramidal geometry is also presented. These results suggest, that the native state of this metallohydrolase may contain a, pentacoordinate zinc ion, which contrasts with the native states of, archetypical zinc hydrolases such as thermolysin and carboxypeptidase A.

About this Structure

2GO4 is a Single protein structure of sequence from Aquifex aeolicus with ZN, CL and TUX as ligands. Full crystallographic information is available from OCA.

Reference

Mechanistic inferences from the binding of ligands to LpxC, a metal-dependent deacetylase., Gennadios HA, Whittington DA, Li X, Fierke CA, Christianson DW, Biochemistry. 2006 Jul 4;45(26):7940-8. PMID:16800620

Page seeded by OCA on Wed Nov 21 11:18:19 2007