'''Crystal structure of Aquifex aeolicus LpxC complexed with TU-514'''
===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.
The line below this paragraph, {{ABSTRACT_PUBMED_16800620}}, adds the Publication Abstract to the page
(as it appears on PubMed at http://www.pubmed.gov), where 16800620 is the PubMed ID number.
-->
{{ABSTRACT_PUBMED_16800620}}
==About this Structure==
==About this Structure==
Line 28:
Line 32:
[[Category: Whittington, D A.]]
[[Category: Whittington, D A.]]
[[Category: Lpxc-inhibitor complex]]
[[Category: Lpxc-inhibitor complex]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 05:19:45 2008''
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 16:18:22 2008''
Revision as of 16:18, 29 July 2008
This article has been automatically seeded. Changes to this page should pertain to the PDB entry only and not to the protein or biomolecule in general.
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
