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Related Concept Videos

Lipids as Anchors01:32

Lipids as Anchors

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In the plasma membrane, the lipids forming the bilayer can also act as an anchor to tether proteins to the membrane. The three main types of lipid anchors found in eukaryotes are – prenyl groups, fatty acyl groups, and glycosylphosphatidylinositol or GPI groups. Prenyl and fatty acyl groups act as anchors on the cytosolic surface of the membrane, whereas GPI anchors proteins on the extracellular side.
The carboxy-terminal of most of the prenylated proteins, such as Ras proteins, contains...
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Tail-anchoring of Proteins in the ER Membrane01:45

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Tail-anchored, or TA, proteins are estimated to make up to 3-5% of membrane proteins found in the eukaryotic cell. Such proteins have a single transmembrane domain located approximately 30 amino acid residues upstream from the C-terminal end. As a result, the signal recognition particle (SRP) cannot guide a TA protein to the ER membrane for cotranslational insertion. Hence, they are integrated into the ER membrane post-translationally using their C-terminal end as the anchor. TA proteins...
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Updated: Jul 11, 2025

Small-Scale Plasma Membrane Preparation for the Analysis of Candida albicans Cdr1-mGFPHis
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Lipid Tales: Optimizing Arylomycin Membrane Anchors.

Michael F T Koehler1, Yi-Chen Chen2, Yongsheng Chen3

  • 1Department of Discovery Chemistry, Genentech, Inc., South San Francisco, California 94080, United States.

ACS Medicinal Chemistry Letters
|November 17, 2023
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Summary
This summary is machine-generated.

Novel arylomycin-based LepB inhibitors show promise against multidrug-resistant Gram-negative bacteria. Optimizing their lipophilic portion is key for effective bacterial inner membrane targeting and SPase inhibition.

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Area of Science:

  • Microbiology
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • Multidrug-resistant bacteria pose a significant global health threat.
  • A critical need exists for new antibiotics targeting Gram-negative bacteria, with no new classes approved in over 50 years.
  • Type I signal peptidase (SPase) is a validated target in Gram-negative bacteria.

Purpose of the Study:

  • To investigate the role of the lipophilic portion of LepB inhibitors (LepBi) in their efficacy.
  • To develop an assessment method for optimizing LepBi properties for Gram-negative bacteria.

Main Methods:

  • LepB inhibitors (LepBi) based on arylomycin natural products were designed.
  • An approach was developed to evaluate the lipophilic portion's impact on plasma protein binding, outer membrane penetration, and inner membrane anchoring.
  • The study focused on facilitating SPase binding within the bacterial inner membrane.

Main Results:

  • The lipophilic portion significantly influences LepBi's interaction with biological membranes and plasma proteins.
  • Successful optimization of the lipophilic moiety is crucial for effective targeting of the bacterial inner membrane.
  • The developed assessment approach provides insights into LepBi behavior.

Conclusions:

  • LepB inhibitors represent a novel class of antibiotics effective against Gram-negative bacteria.
  • Optimization of the lipophilic component is essential for the development of potent LepBi.
  • Findings offer critical insights for designing future antibacterial agents targeting inner membrane-associated bacterial proteins.