Bacteriophage protein PEIP is a potent Bacillus subtilis enolase inhibitor
Kaining Zhang,
Shanshan Li,
Yawen Wang,
Zhihao Wang,
Nancy Mulvenna,
Hang Yang,
Peipei Zhang,
Huan Chen,
Yan Li,
Hongliang Wang,
Yongxiang Gao,
Sivaramesh Wigneshweraraj,
Steve Matthews,
Kaiming Zhang,
Bing Liu
Affiliations
Kaining Zhang
BioBank, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi 710061, China; Institute for Protein Science and Phage Research, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi 710061, China
Shanshan Li
MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China
Yawen Wang
BioBank, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi 710061, China; Institute for Protein Science and Phage Research, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi 710061, China; Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
Zhihao Wang
BioBank, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi 710061, China; Institute for Protein Science and Phage Research, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi 710061, China; MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK
Nancy Mulvenna
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK
Hang Yang
Department of Pathogen Biology and Immunology, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, China
Peipei Zhang
BioBank, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi 710061, China; Institute for Protein Science and Phage Research, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi 710061, China
Huan Chen
BioBank, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi 710061, China; Institute for Protein Science and Phage Research, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi 710061, China
Yan Li
Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei 430030, China
Hongliang Wang
Department of Pathogen Biology and Immunology, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, China
Yongxiang Gao
MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China
Sivaramesh Wigneshweraraj
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK
Steve Matthews
Institute for Protein Science and Phage Research, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi 710061, China; MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK
Kaiming Zhang
MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China; Corresponding author
Bing Liu
BioBank, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi 710061, China; Institute for Protein Science and Phage Research, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi 710061, China; Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China; Corresponding author
Summary: Enolase is a highly conserved enzyme that presents in all organisms capable of glycolysis or fermentation. Its immediate product phosphoenolpyruvate is essential for other important processes like peptidoglycan synthesis and the phosphotransferase system in bacteria. Therefore, enolase inhibitors are of great interest. Here, we report that Gp60, a phage-encoded enolase inhibitor protein (PEIP) of bacteriophage SPO1 for Bacillus subtilis, is an enolase inhibitor. PEIP-expressing bacteria exhibit growth attenuation, thinner cell walls, and safranin color in Gram staining owing to impaired peptidoglycan synthesis. We solve the structure of PEIP-enolase tetramer and show that PEIP disassembles enolase by disrupting the basic dimer unit. The structure reveals that PEIP does not compete for substrate binding but induces a cascade of conformational changes that limit accessibility to the enolase catalytic site. This phage-inspired disassembly of enolase represents an alternative strategy for the development of anti-microbial drugs.
