Structural basis of Zn(II) acquisition mechanism in Pneumococcus

Z Luo1,2,3, J Morey4, A McEwan1,2, C McDevitt4 and B Kobe1,2,3

  1. School of Chemistry and Molecular Biosciences, University of Queensland
  2. Australian Infectious Diseases Research Centre, University of Queensland
  3. Institute for Molecular Biosciences, University of Queensland
  4. Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide

Pneumococcus (Streptococcus pneumoniae) is among the world’s leading bacterial pathogens and is responsible for over 1 million deaths annually. Transition metals, such as Zn(II), have been recognized as essential nutrients for the growth and virulence of pathogenic bacteria in humans. Acquisition of Zn(II) in pneumococcus is supported by the ATP binding cassette transporter AdcBCA, which includes a surface protein AdcA as the initial receptor for Zn(II) recognition. AdcA is a high affinity Zn(II)-specific substrate binding protein with two Zn(II)-binding domains (ZnuA-domain and ZinT-domain) and its imperative role in the survival and pathogenicity of the pneumococcus makes the protein a potential therapeutic target for the development of novel antimicrobial drugs against pneumococcal diseases. However, the lack of experimentally determined structures of AdcA hinders a deeper understanding of the Zn(II) acquisition mechanism in the pneumococcus. Therefore, in this study, we determined a series of high-resolution crystal structures of AdcA and its individual domains by X-ray crystallography. In the structures, both of the AdcA domains possess Zn(II)-binding sites and are capable of capturing Zn(II) with high affinity. Also, the two domains can interact with each other and form a tract of histidine residues connecting their Zn(II)-binding sites. Based on the structures, we hypothesize that the two domains in AdcA work collaboratively to acquire Zn(II) with high efficiency during severe Zn(II) shortage in hosts. The results provide the first structural insights into the mechanism of AdcA-mediated Zn(II) acquisition in the pneumococcus.