| Structural highlights
Function
LPTD_ECOLI Together with LptE, is involved in the assembly of lipopolysaccharide (LPS) at the surface of the outer membrane. Contributes to n-hexane resistance.[HAMAP-Rule:MF_01411][1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Lipopolysaccharides (LPS) are the principal chemical component of the outer leaflet of Gram-negative bacteria and constitute the first barrier of defense against foreign molecules. Inhibition of LPS transport presents a novel concept for antibiotic discovery, and components of the transport bridge are targets of antimicrobial peptides. LptD, a beta-barrel outer membrane protein, the terminal module of the Lpt transport bridge, however, remains largely unexplored as a drug target as its biosynthesis is complicated and screens against membrane proteins are challenging. Herein, we report a computationally designed, soluble E. coli LptD periplasmic epitope mimic, LptDm. We describe an efficient in silico design pipeline that includes verification of interactions of LptD mimics with the cognate ligands LptA and thanatin using nuclear magnetic resonance (NMR) and size-exclusions chromatography (SEC) techniques. A small peptide library demonstrates that LptDm allows for selection of high-affinity binders against LptD, rendering LptD accessible to modern drug discovery approaches.
Computational design of a soluble mimic of the outer membrane LPS transport protein LptD suitable for screening of antibiotics.,Dai W, Hu W, Schuster M, Rozic L, Roschitzki B, Zerbe O Protein Sci. 2026 Jun;35(6):e70626. doi: 10.1002/pro.70626. PMID:42144870[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Braun M, Silhavy TJ. Imp/OstA is required for cell envelope biogenesis in Escherichia coli. Mol Microbiol. 2002 Sep;45(5):1289-302. PMID:12207697
- ↑ Abe S, Okutsu T, Nakajima H, Kakuda N, Ohtsu I, Aono R. n-Hexane sensitivity of Escherichia coli due to low expression of imp/ostA encoding an 87 kDa minor protein associated with the outer membrane. Microbiology. 2003 May;149(Pt 5):1265-73. PMID:12724388
- ↑ Wu T, McCandlish AC, Gronenberg LS, Chng SS, Silhavy TJ, Kahne D. Identification of a protein complex that assembles lipopolysaccharide in the outer membrane of Escherichia coli. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11754-9. Epub 2006 Jul 21. PMID:16861298 doi:https://dx.doi.org/0604744103
- ↑ Sperandeo P, Lau FK, Carpentieri A, De Castro C, Molinaro A, Deho G, Silhavy TJ, Polissi A. Functional analysis of the protein machinery required for transport of lipopolysaccharide to the outer membrane of Escherichia coli. J Bacteriol. 2008 Jul;190(13):4460-9. Epub 2008 Apr 18. PMID:18424520 doi:JB.00270-08
- ↑ Chng SS, Ruiz N, Chimalakonda G, Silhavy TJ, Kahne D. Characterization of the two-protein complex in Escherichia coli responsible for lipopolysaccharide assembly at the outer membrane. Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5363-8. doi:, 10.1073/pnas.0912872107. Epub 2010 Mar 4. PMID:20203010 doi:https://dx.doi.org/10.1073/pnas.0912872107
- ↑ Haarmann R, Ibrahim M, Stevanovic M, Bredemeier R, Schleiff E. The properties of the outer membrane localized Lipid A transporter LptD. J Phys Condens Matter. 2010 Nov 17;22(45):454124. doi:, 10.1088/0953-8984/22/45/454124. Epub 2010 Oct 29. PMID:21339611 doi:https://dx.doi.org/10.1088/0953-8984/22/45/454124
- ↑ Sampson BA, Misra R, Benson SA. Identification and characterization of a new gene of Escherichia coli K-12 involved in outer membrane permeability. Genetics. 1989 Jul;122(3):491-501. PMID:2547691
- ↑ Aono R, Negishi T, Nakajima H. Cloning of organic solvent tolerance gene ostA that determines n-hexane tolerance level in Escherichia coli. Appl Environ Microbiol. 1994 Dec;60(12):4624-6. PMID:7811102
- ↑ Dai W, Hu W, Schuster M, Rozic L, Roschitzki B, Zerbe O. Computational design of a soluble mimic of the outer membrane LPS transport protein LptD suitable for screening of antibiotics. Protein Sci. 2026 Jun;35(6):e70626. doi: 10.1002/pro.70626. PMID:42144870 doi:https://dx.doi.org/10.1002/pro.70626
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