Structural basis of Zn(II) induced metal detoxification and antibiotic resistance by histidine kinase CzcS in Pseudomonas aeruginosa

PLoS Pathogens

Weizhong Chen¹  Yafeng He¹  Tianbiao Wei¹  Hao Chen¹  Xichun Liu¹  Qingyuan Hu¹  Dan Wang¹  Shanqing Huang¹  Hong Sang²  Jianhua Gan³ 

[1]Coordination Chemistry Institute and the State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing, P.R. China

[2]Jinling Hospital, Department of Dermatology, Medical School of Nanjing University, Nanjing University, Nanjing, P. R. China

[3]State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, Shanghai, China

关键词: Pseudomonas aeruginosa;    Antibiotic resistance;    Antibiotics;    Proline;    Zinc;    Dimers (Chemical physics);    Dimerization;    Detoxification;   

DOI  :  10.1371/journal.ppat.1006533

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Pseudomonas aeruginosa (P. aeruginosa) is a major opportunistic human pathogen, causing serious nosocomial infections among immunocompromised patients by multi-determinant virulence and high antibiotic resistance. The CzcR-CzcS signal transduction system in P. aeruginosa is primarily involved in metal detoxification and antibiotic resistance through co-regulating cross-resistance between Zn(II) and carbapenem antibiotics. Although the intracellular regulatory pathway is well-established, the mechanism by which extracellular sensor domain of histidine kinase (HK) CzcS responds to Zn(II) stimulus to trigger downstream signal transduction remains unclear. Here we determined the crystal structure of the CzcS sensor domain (CzcS SD) in complex with Zn(II) at 1.7 Å resolution. This is the first three-dimensional structural view of Zn(II)-sensor domain of the two-component system (TCS). The CzcS SD is of α/β-fold in nature, and it senses the Zn(II) stimulus at micromole level in a tetrahedral geometry through its symmetry-related residues (His55 and Asp60) on the dimer interface. Though the CzcS SD resembles the PhoQ-DcuS-CitA (PDC) superfamily member, it interacts with the effector in a novel domain with the N-terminal α-helices rather than the conserved β-sheets pocket. The dimerization of the N-terminal H1 and H1’ α-helices is of primary importance for the activity of HK CzcS. This study provides preliminary insight into the molecular mechanism of Zn(II) sensing and signaling transduction by the HK CzcS, which will be beneficial to understand how the pathogen P. aeruginosa resists to high levels of heavy metals and antimicrobial agents.

【 授权许可】

CC BY