6V1N

CSP1-E1A-cyc(Dap6E10)

Summary for 6V1N

• Entry DOI: 10.2210/pdb6v1n/pdb
• NMR Information: BMRB: 30690
• Descriptor: Competence-stimulating peptide type 1 (1 entity in total)
• Functional Keywords: modulator, quorum sensing, biosynthetic protein
• Biological source: Streptococcus pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 2160.65

Authors

Yang, Y. (deposition date: 2019-11-20, release date: 2020-01-08, Last modification date: 2020-02-05)

Primary citation

Yang, Y.,Lin, J.,Harrington, A.,Cornilescu, G.,Lau, G.W.,Tal-Gan, Y.
Designing cyclic competence-stimulating peptide (CSP) analogs with pan-group quorum-sensing inhibition activity inStreptococcus pneumoniae.
Proc.Natl.Acad.Sci.USA, 117:1689-1699, 2020

PubMed Abstract: is an opportunistic human pathogen that utilizes the competence regulon, a quorum-sensing circuitry, to acquire antibiotic resistance genes and initiate its attack on the human host. Interception of the competence regulon can therefore be utilized to study cell-cell communication and behavioral changes, as well as attenuate infectivity. Herein we report the design and synthesis of cyclic dominant negative competence-stimulating peptide (dnCSP) analogs capable of intercepting the competence regulon in both specificity groups with activities at the low nanomolar range. Structural analysis of lead analogs provided important insights as to the molecular mechanism that drives CSP receptor binding and revealed that the pan-group cyclic CSPs exhibit a chimeric hydrophobic patch conformation that resembles the hydrophobic patches required for both ComD1 and ComD2 binding. Moreover, the lead cyclic dnCSP, CSP1-E1A-cyc(Dap6E10), was found to possess superior pharmacological properties, including improved resistance to enzymatic degradation, while remaining nontoxic. Lastly, CSP1-E1A-cyc(Dap6E10) was capable of attenuating mouse mortality during acute pneumonia caused by both group 1 and group 2 strains. This cyclic pan-group dnCSP is therefore a promising drug lead scaffold against infections that could be administered individually or utilized in combination therapy to augment the effects of current antimicrobial agents.

PubMed: 31915298
DOI: 10.1073/pnas.1915812117

Experimental method

SOLUTION NMR