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High resolution crystal structure of the catalytic domain of MCR-1
Guixing Ma1, Yifan Zhu1, Zhicheng Yu1
1Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen 518055, China.
Abstract:
The newly identified mobile colistin resistant gene (mcr-1) rapidly spread among different bacterial strains and confers colistin resistance to its host, which has become a global concern. Based on sequence alignment, MCR-1 should be a phosphoethanolamine transferase, members of the YhjW/YjdB/YijP superfamily and catalyze the addition of phosphoethanolamine to lipid A, which needs to be validated experimentally. Here we report the first high-resolution crystal structure of the C-terminal catalytic domain of MCR-1 (MCR-1C) in its native state. The active pocket of native MCR-1C depicts unphosphorylated nucleophilic residue Thr285 in coordination with two Zinc ions and water molecules. A flexible adjacent active site loop (aa: Lys348-365) pose an open conformation compared to its structural homologues, suggesting of an open substrate entry channel. Taken together, this structure sets ground for further study of substrate binding and MCR-1 catalytic mechanism in development of potential therapeutic agents.
Insights
The mobile colistin resistance gene (mcr-1) is a growing global threat. This study reveals the crystal structure of the MCR-1 catalytic domain, offering insights into its function and potential therapeutic targets.
Area of Science:
- Microbiology
- Structural Biology
- Drug Discovery
Background:
- The mobile colistin resistance gene (mcr-1) confers resistance to colistin, a critical antibiotic.
- Rapid spread of mcr-1 among bacteria poses a significant global health concern.
- MCR-1 is predicted to be a phosphoethanolamine transferase, but experimental validation is needed.
Purpose of the Study:
- To determine the high-resolution crystal structure of the MCR-1 catalytic domain (MCR-1C) in its native state.
- To elucidate the structural basis for MCR-1's enzymatic activity.
- To provide a foundation for developing novel therapeutic strategies against colistin-resistant bacteria.
Main Methods:
- X-ray crystallography was used to determine the structure of MCR-1C.
- Sequence alignment was performed to identify conserved domains and residues.
- Structural analysis focused on the active site and substrate-binding regions.
Main Results:
- The first high-resolution crystal structure of the native MCR-1C is reported.
- The active site features an unphosphorylated Thr285 coordinated with two Zinc ions and water molecules.
- A flexible active site loop suggests an open conformation, facilitating substrate entry.
Conclusions:
- The determined MCR-1C structure provides crucial insights into its catalytic mechanism.
- The findings pave the way for understanding substrate binding and developing inhibitors.
- This structural information is vital for combating the spread of colistin resistance.
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