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Related Concept Videos

Carrier-Mediated Transport01:06

Carrier-Mediated Transport

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Carrier-mediated transport is a pivotal process in drug absorption, particularly for lipid-insoluble drugs, and encompasses facilitated diffusion and active transport. Facilitated diffusion allows drugs to move along their concentration gradient without energy expenditure, while active transport utilizes ATP to drive drug movement against this gradient.
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
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Drug Absorption Mechanism: Carrier-Mediated Membrane Transport01:19

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Certain large, lipid-insoluble drug molecules that resemble amino acids, peptides, or glucose, require specialized carrier proteins to facilitate their diffusion across cell membranes. This transport can occur through either facilitated diffusion, which does not require energy input, or active transport, which does require energy input.
Facilitated diffusion is a passive process that utilizes human Solute Carrier (SLC) transporters. These transporters bind to the drug, undergo structural...
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Primary Active Transport01:29

Primary Active Transport

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In contrast to passive transport, active transport involves a substance being moved through membranes in a direction against its concentration or electrochemical gradient. There are two types of active transport: primary active transport and secondary active transport. Primary active transport utilizes chemical energy from ATP to drive protein pumps embedded in the cell membrane. With energy from ATP, the pumps transport ions against their electrochemical gradients—a direction they would...
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Active Transport01:14

Active Transport

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Active transport is a critical biological process that allows cells to move solutes against an electrochemical gradient. This process requires direct energy input and is characterized by its selectivity, saturability, and susceptibility to competitive inhibition.
Primary active transporters, like Na+, K+ and -ATPase, directly utilize ATP to move ions across the membrane. These transporters play significant roles in various physiological processes. For instance, Na+, K+ and -ATPase maintain...
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Membrane Transporters01:31

Membrane Transporters

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Transporters are essential membrane transport proteins with functions related to cell nutrition, homeostasis, communication, etc. Approximately 7% of all genes in the human genome code for transporters or transporter-related proteins.
Transporters are mainly composed of alpha-helices, built from bundles of ten or more helices traversing the plasma membrane. The solute-binding sites are located midway, where some of the helices are broken or distorted, making space for the binding site through...
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Pore Transport and Ion-Pair Transport01:17

Pore Transport and Ion-Pair Transport

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Pore transport and ion-pair formation are critical mechanisms for the absorption and distribution of drugs in the body.
Pore transport, also known as convective transport, is a process where small molecules like urea, water, and sugars rapidly cross cell membranes as though there were channels or pores in the membrane. Although direct microscopic evidence is limited  but the concept of pores or channels is widely accepted based on physiological evidence. Despite the lack of direct...
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Affinity-directed substrate/H+-antiport by a MATE transporter.

Koh Takeuchi1, Takumi Ueda2, Misaki Imai3

  • 1Graduate School of Pharmacological Sciences, The University of Tokyo, Hongo, Bunkyo, Tokyo 113-0033, Japan; Molecular Profiling Research Center for Drug Discovery and Cellular Molecular Biotechnology Research Institute, National Institute of Advanced Science and Technology, Aomi, Koto, Tokyo 135-0063, Japan.

Structure (London, England : 1993)
|May 30, 2024
PubMed
Summary

Multidrug and toxin extrusion (MATE) transporters use ion gradients to expel toxins. This study reveals MATE transporters operate via an affinity-directed mechanism, coupling substrate binding to proton movement for efficient excretion.

Keywords:
MATE transporterantiporterconformational equilibriumdynamicsmembrane proteinsolution NMRstructure

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Membrane Transport

Background:

  • Multidrug and toxin extrusion (MATE) transporters are crucial for cellular detoxification.
  • While MATE transporter structures exist, the mechanism of substrate export coupled to ion influx is unclear.

Purpose of the Study:

  • To elucidate the transport mechanism of MATE family transporters.
  • To investigate the structural dynamics and substrate binding of Pyrococcus furiosus MATE (PfMATE).

Main Methods:

  • Solution nuclear magnetic resonance (NMR) spectroscopy of PfMATE.
  • Site-directed mutagenesis of acidic residues to probe protonation states and conformational changes.

Main Results:

  • PfMATE exists in an equilibrium between inward-facing (IF) and outward-facing (OF) conformations, regulated by Glu163 protonation.
  • Substrate recognition occurs with mid-μM affinity in the protonated IF conformation.
  • The OF conformation displays weak mM substrate affinity, facilitating extracellular release.

Conclusions:

  • PfMATE functions as an affinity-directed H+/substrate antiporter.
  • Protonation of the IF conformation is essential for high-affinity substrate binding.
  • Subsequent proton release drives H+-coupled substrate excretion, elucidating the MATE transport mechanism.