Structural highlights
Publication Abstract from PubMedPhenol-soluble modulin alpha3 (PSMalpha3) is a cytotoxic peptide secreted by virulent strains of Staphylococcus aureus. We used a stereochemical strategy to examine the mechanism of PSMalpha3-mediated toxicity. One hypothesis is that PSMalpha3 toxicity requires fibril formation; an alternative is that toxicity is caused by soluble forms of PSMalpha3, possibly oligomeric. We find that the unnatural enantiomer (D residues) displays cytotoxicity comparable to that of L-PSMalpha3. Racemic PSMalpha3 is similarly toxic to enantiopure PSMalpha3 (L or D) under some conditions, but the toxicity is lost under conditions that cause racemic PSMalpha3 to aggregate. A crystal structure of racemic PSMalpha3-NH2 displays an alpha-helical secondary structure and a packing pattern that is reminiscent of the cross-alpha arrangement recently discovered in crystals of L-PSMalpha3. Our data suggest that the cytotoxicity of PSMalpha3 does not depend on stereospecific engagement of a target protein or other chiral macromolecule, an observation that supports a mechanism based on membrane disruption. In addition, our data support the hypothesis that toxicity is exerted by a soluble form rather than an insoluble fibrillar form. Use of a Stereochemical Strategy To Probe the Mechanism of Phenol-Soluble Modulin alpha3 Toxicity.,Yao Z, Cary BP, Bingman CA, Wang C, Kreitler DF, Satyshur KA, Forest KT, Gellman SH J Am Chem Soc. 2019 May 15;141(19):7660-7664. doi: 10.1021/jacs.9b00349. Epub, 2019 May 2. PMID:31045358[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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