6JMP

Crystal Structure of a Non-hemolytic Pneumolysin from Streptococcus pneumoniae strain ST306

Summary for 6JMP

• Entry DOI: 10.2210/pdb6jmp/pdb
• Descriptor: Thiol-activated cytolysin, GLYCEROL (3 entities in total)
• Functional Keywords: cholesterol dependent cytolysin, toxin, pneumolysin, non-pore forming, non-hemolytic, membrane
• Biological source: Streptococcus pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 53129.24

Authors

Badgujar, D.C.,Bhaumik, P. (deposition date: 2019-03-13, release date: 2020-09-09, Last modification date: 2023-11-22)

Primary citation

Badgujar, D.C.,Anil, A.,Green, A.E.,Surve, M.V.,Madhavan, S.,Beckett, A.,Prior, I.A.,Godsora, B.K.,Patil, S.B.,More, P.K.,Sarkar, S.G.,Mitchell, A.,Banerjee, R.,Phale, P.S.,Mitchell, T.J.,Neill, D.R.,Bhaumik, P.,Banerjee, A.
Structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellular lifestyle.
Plos Pathog., 16:e1009016-e1009016, 2020

PubMed Abstract: The opportunistic pathogen Streptococcus pneumoniae has dual lifestyles: one of an asymptomatic colonizer in the human nasopharynx and the other of a deadly pathogen invading sterile host compartments. The latter triggers an overwhelming inflammatory response, partly driven via pore forming activity of the cholesterol dependent cytolysin (CDC), pneumolysin. Although pneumolysin-induced inflammation drives person-to-person transmission from nasopharynx, the primary reservoir for pneumococcus, it also contributes to high mortality rates, creating a bottleneck that hampers widespread bacterial dissemination, thus acting as a double-edged sword. Serotype 1 ST306, a widespread pneumococcal clone, harbours a non-hemolytic variant of pneumolysin (Ply-NH). Performing crystal structure analysis of Ply-NH, we identified Y150H and T172I as key substitutions responsible for loss of its pore forming activity. We uncovered a novel inter-molecular cation-π interaction, governing formation of the transmembrane β-hairpins (TMH) in the pore state of Ply, which can be extended to other CDCs. H150 in Ply-NH disrupts this interaction, while I172 provides structural rigidity to domain-3, through hydrophobic interactions, inhibiting TMH formation. Loss of pore forming activity enabled improved cellular invasion and autophagy evasion, promoting an atypical intracellular lifestyle for pneumococcus, a finding that was corroborated in in vivo infection models. Attenuation of inflammatory responses and tissue damage promoted tolerance of Ply-NH-expressing pneumococcus in the lower respiratory tract. Adoption of this altered lifestyle may be necessary for ST306 due to its limited nasopharyngeal carriage, with Ply-NH, aided partly by loss of its pore forming ability, facilitating a benign association of SPN in an alternative, intracellular host niche.

PubMed: 33216805
DOI: 10.1371/journal.ppat.1009016

Experimental method

X-RAY DIFFRACTION (2.2 Å)