4.7 Article

Crystal Structure and Pathophysiological Role of the Pneumococcal Nucleoside-binding Protein PnrA

期刊

JOURNAL OF MOLECULAR BIOLOGY
卷 433, 期 2, 页码 -

出版社

ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2020.11.022

关键词

transporter; nucleoside; pneumococci; virulence; physiology; crystal structure

资金

  1. Deutsche Forschungsgemeinschaft DFG [GRK 1870]
  2. Bundesministerium fur Bildung und Forschung (BMBF) - Zwanzig20 InfectControl 2020 - project VacoME [FKZ 03ZZ0816A]
  3. Federal Excellence Initiative of Mecklenburg Western Pomerania
  4. European Social Fund (ESF) Grant KoInfekt [ESF_14-BM-A55-0001_16]
  5. Spanish Ministry of Science, Innovation and Universities [BFU201790030-P]

向作者/读者索取更多资源

PnrA is a nucleoside-binding protein in Streptococcus pneumoniae, which preferentially binds purine ribonucleosides and plays a crucial role in the virulence of the bacteria during infection. Its structure and interactions with nucleosides have been revealed through crystal structures, shedding light on its importance in pneumococcal fitness.
Nucleotides are important for RNA and DNA synthesis and, despite a de novo synthesis by bacteria, uptake systems are crucial. Streptococcus pneumoniae, a facultative human pathogen, produces a surface-exposed nucleoside-binding protein, PnrA, as part of an ABC transporter system. Here we demonstrate the binding affinity of PnrA to nucleosides adenosine, guanosine, cytidine, thymidine and uridine by microscale thermophoresis and indicate the consumption of adenosine and guanosine by H-1 NM R spectroscopy. In a series of five crystal structures we revealed the PnrA structure and provide insights into how PnrA can bind purine and pyrimidine ribonucleosides but with preference for purine ribonucleosides. Crystal structures of PnrA:nucleoside complexes unveil a clear pattern of interactions in which both the N-and C- domains of PnrA contribute. The ribose moiety is strongly recognized through a conserved network of H-bond interactions, while plasticity in loop 27-36 is essential to bind purine- or pyrimidine-based nucleosides. Further, we deciphered the role of PnrA in pneumococcal fitness in infection experiments. Phagocytosis experiments did not show a clear difference in phagocytosis between PnrA-deficient and wild-type pneumococci. In the acute pneumonia infection model the deficiency of PnrA attenuated moderately virulence of the mutant, which is indicated by a delay in the development of severe lung infections. Importantly, we confirmed the loss of fitness in co-infections, where the wild-type out-competed the pnrA-mutant. In conclusion, we present the PnrA structure in complex with individual nucleosides and show that the consumption of adenosine and guanosine under infection conditions is required for virulence. (C) 2020 Elsevier Ltd. All rights reserved.

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