Structural highlights
Publication Abstract from PubMedThe bacterial second messenger cyclic diguanylate (c-di-GMP) regulates a wide range of cellular functions from biofilm formation to growth and survival. Targeting a second-messenger network is challenging because the system involves a multitude of components with often overlapping functions. Here, we present a strategy to intercept c-di-GMP signaling pathways by directly targeting the second messenger. For this, we developed a c-di-GMP-sequestering peptide (CSP) that was derived from a CheY-like c-di-GMP effector protein. CSP binds c-di-GMP with submicromolar affinity. The elucidation of the CSPc-di-GMP complex structure by NMR identified a linear c-di-GMP-binding motif, in which a self-intercalated c-di-GMP dimer is tightly bound by a network of H bonds and pi-stacking interactions involving arginine and aromatic residues. Structure-based mutagenesis yielded a variant with considerably higher, low-nanomolar affinity, which subsequently was shortened to 19 residues with almost uncompromised affinity. We demonstrate that endogenously expressed CSP intercepts c-di-GMP signaling and effectively inhibits biofilm formation in Pseudomonas aeruginosa, the most widely used model for serious biofilm-associated medical implications. Intercepting second-messenger signaling by rationally designed peptides sequestering c-di-GMP.,Hee CS, Habazettl J, Schmutz C, Schirmer T, Jenal U, Grzesiek S Proc Natl Acad Sci U S A. 2020 Jul 21;117(29):17211-17220. doi:, 10.1073/pnas.2001232117. Epub 2020 Jul 1. PMID:32611811[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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