1. The Complex Structure of Protein AaLpxC from Aquifex aeolicus with ACHN-975 Molecule Suggests an Inhibitory Mechanism at Atomic-Level against Gram-Negative Bacteria
- Author
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Xiao Feng, Fan Shuai, Maocai Yan, Guangteng Wu, Yuanyuan Jin, Li Danyang, Zhaoyong Yang, Guangxin Lv, and Yucheng Wang
- Subjects
Gram-negative bacteria ,Protein Conformation ,Stereochemistry ,Pharmaceutical Science ,Calorimetry ,Crystallography, X-Ray ,01 natural sciences ,Article ,LpxC ,Drug design ,Amidohydrolases ,Analytical Chemistry ,lcsh:QD241-441 ,Lipid A ,03 medical and health sciences ,X-ray Crystallography ,Bacterial Proteins ,lcsh:Organic chemistry ,Gram-Negative Bacteria ,Drug Discovery ,Physical and Theoretical Chemistry ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Aquifex aeolicus ,Binding Sites ,Crystal structure ITC ,biology ,010405 organic chemistry ,Organic Chemistry ,ACHN-975 ,Active site ,Isothermal titration calorimetry ,biology.organism_classification ,Anti-Bacterial Agents ,0104 chemical sciences ,Aquifex ,Enzyme ,chemistry ,Chemistry (miscellaneous) ,Benzamides ,biology.protein ,Thermodynamics ,Molecular Medicine ,Bacterial outer membrane ,Bacteria - Abstract
New drugs with novel antibacterial targets for Gram-negative bacterial pathogens are desperately needed. The protein LpxC is a vital enzyme for the biosynthesis of lipid A, an outer membrane component of Gram-negative bacterial pathogens. The ACHN-975 molecule has high enzymatic inhibitory capacity against the infectious diseases, which are caused by multidrug-resistant bacteria, but clinical research was halted because of its inflammatory response in previous studies. In this work, the structure of the recombinant UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase from Aquifex aeolicus in complex with ACHN-975 was determined to a resolution at 1.21 Å. According to the solved complex structure, ACHN-975 was docked into the AaLpxC’s active site, which occupied the site of AaLpxC substrate. Hydroxamate group of ACHN-975 forms five-valenced coordination with resides His74, His226, Asp230, and the long chain part of ACHN-975 containing the rigid alkynyl groups docked in further to interact with the hydrophobic area of AaLpxC. We employed isothermal titration calorimetry for the measurement of affinity between AaLpxC mutants and ACHN-975, and the results manifest the key residues (His74, Thr179, Tyr212, His226, Asp230 and His253) for interaction. The determined AaLpxC crystal structure in complex with ACHN-975 is expected to serve as a guidance and basis for the design and optimization of molecular structures of ACHN-975 analogues to develop novel drug candidates against Gram-negative bacteria.
- Published
- 2021
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