9CO2

Crystal structure of BamA in complex with the PTB2 open-state inhibitor (anisotropic data set)

Summary for 9CO2

• Entry DOI: 10.2210/pdb9co2/pdb
• Descriptor: Outer membrane protein assembly factor BamA, PTB2 circular peptide (2 entities in total)
• Functional Keywords: protein crystal structure, circular peptide, membrane protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 8
• Total formula weight: 178674.50

Authors

Sun, D.,Payandeh, J. (deposition date: 2024-07-16, release date: 2025-01-15)

Primary citation

Sun, D.,Storek, K.M.,Tegunov, D.,Yang, Y.,Arthur, C.P.,Johnson, M.,Quinn, J.G.,Liu, W.,Han, G.,Girgis, H.S.,Alexander, M.K.,Murchison, A.K.,Shriver, S.,Tam, C.,Ijiri, H.,Inaba, H.,Sano, T.,Yanagida, H.,Nishikawa, J.,Heise, C.E.,Fairbrother, W.J.,Tan, M.W.,Skelton, N.,Sandoval, W.,Sellers, B.D.,Ciferri, C.,Smith, P.A.,Reid, P.C.,Cunningham, C.N.,Rutherford, S.T.,Payandeh, J.
The discovery and structural basis of two distinct state-dependent inhibitors of BamA.
Nat Commun, 15:8718-8718, 2024

PubMed 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.

PubMed: 39379361
DOI: 10.1038/s41467-024-52512-1

Experimental method

X-RAY DIFFRACTION (2.75 Å)