| Autor: |
Dawei Sun, Kelly M. Storek, Dimitry Tegunov, Ying Yang, Christopher P. Arthur, Matthew Johnson, John G. Quinn, Weijing Liu, Guanghui Han, Hany S. Girgis, Mary Kate Alexander, Austin K. Murchison, Stephanie Shriver, Christine Tam, Hiroshi Ijiri, Hiroko Inaba, Tatsuya Sano, Hayato Yanagida, Junichi Nishikawa, Christopher E. Heise, Wayne J. Fairbrother, Man-Wah Tan, Nicholas Skelton, Wendy Sandoval, Benjamin D. Sellers, Claudio Ciferri, Peter A. Smith, Patrick C. Reid, Christian N. Cunningham, Steven T. Rutherford, Jian Payandeh |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 15, Iss 1, Pp 1-15 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-024-52512-1 |
| Popis: |
Abstract BamA is the central component of the essential β-barrel assembly machine (BAM), a conserved multi-subunit complex that dynamically inserts and folds β-barrel proteins into the outer membrane of Gram-negative bacteria. Despite recent advances in our mechanistic and structural understanding of BamA, there are few potent and selective tool molecules that can bind to and modulate BamA activity. Here, we explored in vitro selection methods and different BamA/BAM protein formulations to discover peptide macrocycles that kill Escherichia coli by targeting extreme conformational states of BamA. Our studies show that Peptide Targeting BamA-1 (PTB1) targets an extracellular divalent cation-dependent binding site and locks BamA into a closed lateral gate conformation. By contrast, PTB2 targets a luminal binding site and traps BamA into an open lateral gate conformation. Our results will inform future antibiotic discovery efforts targeting BamA and provide a template to prospectively discover modulators of other dynamic integral membrane proteins. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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