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Updated: Aug 9, 2026
10:28
A Semi-High-Throughput Adaptation of the NADH-Coupled ATPase Assay for Screening Small Molecule Inhibitors
Published on: August 17, 2019
New light on multidrug binding by an ATP-binding-cassette transporter
Richard A Shilling1, Henrietta Venter, Saroj Velamakanni
1Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, UK, CB2 1PD.
Trends in Pharmacological Sciences
|March 21, 2006
Summary
ATP-binding-cassette (ABC) multidrug transporters, crucial for drug resistance, have unclear molecular mechanisms. New structural insights reveal specific
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- ATP-binding-cassette (ABC) transporters mediate multidrug resistance by extruding drugs from cells.
- The precise molecular mechanisms of drug binding and transport by ABC transporters remain poorly understood.
- Previous genetic studies on P-glycoproteins identified numerous mutations affecting drug resistance but lacked structural context.
Purpose of the Study:
- To elucidate the molecular basis of drug binding and transport in ABC multidrug transporters.
- To correlate existing mutagenesis data with newly available three-dimensional structural information of transporters.
- To identify specific regions within P-glycoprotein involved in drug specificity.
Main Methods:
- Comparative analysis of mutagenesis data with X-ray crystallographic structures.
- Utilizing structural data of bacterial homologue MsbA and an MsbA-based homology model of human P-glycoprotein.
- Mapping amino acid mutations onto the three-dimensional transporter structures.
Main Results:
- Mutations affecting drug specificity in P-glycoproteins are localized to specific three-dimensional 'hotspot' regions.
- These 'hotspot' regions are situated within the membrane domains of the transporter.
- Structural analysis provides a framework for understanding genotype-phenotype relationships in multidrug resistance.
Conclusions:
- Three-dimensional structural information is critical for interpreting the functional significance of mutations in ABC transporters.
- Specific 'hotspot' regions in the membrane domains are key determinants of drug specificity.
- This study advances our understanding of the molecular mechanisms underlying multidrug resistance mediated by P-glycoproteins.
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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:
01:31ABC Transporters: Exporter
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...
01:06Carrier-Mediated Transport
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.
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01:48ATP Synthase: Mechanism
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01:44The Significance of Membrane Transport
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