Related Experiment Video
Updated: Nov 9, 2025
09:35
Real Time Measurements of Membrane Protein:Receptor Interactions Using Surface Plasmon Resonance SPR
Published on: November 29, 2014
23.1K
Structural Basis of Drug Recognition by the Multidrug Transporter ABCG2.
Julia Kowal1, Dongchun Ni2, Scott M Jackson1
1Institute of Molecular Biology and Biophysics, ETH Zurich, Switzerland.
Journal of Molecular Biology
|April 10, 2021
Summary
Structural insights into the ABCG2 transporter reveal how it binds anticancer drugs like tariquidar, topotecan, and mitoxantrone. This understanding of ABCG2
Area of Science:
- Structural Biology
- Biochemistry
- Pharmacology
Background:
- ABCG2 (ATP-binding cassette transporter G2) influences drug pharmacokinetics and cancer multidrug resistance.
- Previous structural studies elucidated ABCG2's interaction with endogenous substrates but lacked resolution for exogenous compounds.
Purpose of the Study:
- To determine high-resolution structures of human ABCG2 bound to anticancer drugs.
- To elucidate the molecular mechanisms of drug recognition and binding by ABCG2.
Main Methods:
- Cryo-electron microscopy (cryo-EM) of nanodisc-reconstituted human ABCG2.
- Utilized Fab fragments of the 5D3 monoclonal antibody to enhance structural resolution.
- Performed mutagenesis and 3D variability analyses.
Main Results:
- Presented three cryo-EM structures of ABCG2 bound to tariquidar, topotecan, and mitoxantrone.
- Identified specific binding sites and conformations for each drug within the ABCG2 binding pocket.
- Observed reduced nucleotide binding domain (NBD) dynamics upon substrate binding, correlating with ATPase stimulation.
Conclusions:
- Provided high-resolution structural basis for how ABCG2 binds and transports anticancer drugs.
- Elucidated the differentiation between ABCG2 inhibitors and substrates at a molecular level.
- Findings may guide the rational design of novel ABCG2 modulators for cancer therapy.
Related Concept Videos
01:31ABC Transporters: Exporter
5.6K
ATP-binding cassette or ABC transporter is the largest superfamily of integral membrane proteins. The transporters have transmembrane-binding domains (TMDs) and nucleotide-binding domains (NBDs). The TMDs are specific to their substrates, whereas the NBDs are similar to engines that complete ATP hydrolysis to complete the substrate transport. They can be full transporters consisting of two TMDs and NBDs, half transporters with one TMD and NBD, while some encoded with a single TMD or NBD are...
5.6K
01:27ABC Transporters: Importer
3.1K
ATP-binding cassette or ABC transporters are a class of ATP-driven pumps that hydrolyze ATP to move solutes across the membrane. They can be grouped into importers and exporters. While exporters are present in all domains of life, importers exist only in bacteria and some plants.
In bacteria, based on the number of transmembrane helices and the chemical nature of their substrates, the ABC importers can be divided into three types:
In bacteria, based on the number of transmembrane helices and the chemical nature of their substrates, the ABC importers can be divided into three types:
3.1K
01:06Carrier-Mediated Transport
731
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...
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
731
01:19Drug Absorption Mechanism: Carrier-Mediated Membrane Transport
5.2K
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...
Facilitated diffusion is a passive process that utilizes human Solute Carrier (SLC) transporters. These transporters bind to the drug, undergo structural...
5.2K
01:24Cellular Membranes and Drug Transport
1.1K
Drugs must traverse multiple biological barriers, such as multi-layered skin, single-layered intestinal epithelium, and the plasma membrane, to reach their target sites within the body. The plasma membrane, a highly structured composite of phospholipids, carbohydrates, and proteins, is the cell's protective boundary, facilitating selective substance exchange.
Phospholipids arrange themselves into a bilayer, with hydrophilic heads oriented outward and hydrophobic tails facing inward.
Phospholipids arrange themselves into a bilayer, with hydrophilic heads oriented outward and hydrophobic tails facing inward.
1.1K
01:31Membrane Transporters
15.7K
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...
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...
15.7K