Structure-based design of a periplasmic binding protein antagonist that prevents domain closure

M. Jack Borrok, Yimin Zhu, Katrina T. Forest, Laura L. Kiessling

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Many receptors undergo ligand-induced conformational changes to initiate signal transduction. Periplasmic binding proteins (PBPs) are bacterial receptors that exhibit dramatic conformational changes upon ligand binding. These proteins mediate a wide variety of fundamental processes including transport, chemotaxis, and quorum sensing. Despite the importance of these receptors, no PBP antagonists have been identified and characterized. In this study, we identify 3-O-methyl-D-glucose as an antagonist of glucose/galactose-binding protein and demonstrate that it inhibits glucose chemotaxis in E. coli. Using small-angle X-ray scattering and X-ray crystallography, we show that this antagonist acts as a wedge. It prevents the large-scale domain closure that gives rise to the active signaling state. Guided by these results and the structures of open and closed glucose/ galactose-binding protein, we designed and synthesized an antagonist composed of two linked glucose residues. These findings provide a blueprint for the design of new bacterial PBP inhibitors. Given the key role of PBPs in microbial physiology, we anticipate that PBP antagonists will have widespread uses as probes and antimicrobial agents.

Original languageEnglish (US)
Pages (from-to)447-456
Number of pages10
JournalACS chemical biology
Volume4
Issue number6
DOIs
StatePublished - Jun 19 2009

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine

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