The ABC Transporters: Structural Insights into Drug Transport

Ford, Robert C.; Kamis, Alhaji Bukar; Kerr, Ian D.; Callaghan, Richard

doi:10.1002/9783527627424.ch1

Cited by 8 publications

(10 citation statements)

References 226 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ABC transporters are found in all living organisms and are characterized by the presence of a highly conserved signature (LSGGQ) motif . In human genome, 49 ABC proteins are known from which 48 appear to be functional.…”

Section: Multidrug Resistance and Abc Transportersmentioning

confidence: 99%

“…The most frequent TMD configuration comprises 12 α ‐helices in a 2 × 6 arrangement, although transporters may have up to 2 × 10 helices (as in BtuCD, the B12 vitamin transport uptaker), whereas NBDs are organized in an head‐to‐tail manner to allow the formation of the ATP‐binding site at the subunit interface . This nucleotide‐binding site is formed by the highly conserved Walker‐A (GXXGXGKS/T) and Walker‐B motifs (ΦΦΦΦDE, where Φ is any aliphatic residue) of one NBD and the signature motif of the opposing NBD . Although some transporters of ABC family have well‐characterized roles in several diseases (Table ), others are constitutively expressed in many tissues and appear to be particularly related with MDR in cancer, as the cases of P‐glycoprotein (P‐gp, ABCB1), multidrug resistance ‐associated protein 1 (MRP1, ABCC1), or breast cancer resistance protein (BCRP, ABCG2)…”

Section: Multidrug Resistance and Abc Transportersmentioning

confidence: 99%

“…The first plausible explanation for the efflux mechanism in these types of transporters was formulated in the 1960s and has become intensively studied over the years. In its most simple model, efflux pumps are comprised by a (1) large flexible internal chamber that corresponds to the drug‐binding site (DBS) and (2) an ATP‐binding site that induce conformational changes essential for the efflux . The DBS, when in its basal configuration, possesses a high affinity toward the substrate and is intrinsically flexible to allow the binding of multiple drugs through an induced‐fit mechanism that simultaneously favors ATP binding and NBD dimerization .…”

Section: Multidrug Resistance and Abc Transportersmentioning

confidence: 99%

See 2 more Smart Citations

Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

Ferreira

Santos

2014

WIREs Comput Mol Sci

View full text Add to dashboard Cite

One of the greatest threats to cancer treatment is the development, by some tumors, of resistance to the pharmacological action of several structurally unrelated cytotoxic agents-multidrug resistance (MDR). As P-glycoprotein (P-gp) is one of the most studied ATP-dependent efflux pumps that are frequently involved in drug efflux from cancer cells, the development of MDR modulators with the ability to inhibit P-gp efflux is considered a promising approach for overcoming MDR. However, the development of P-gp modulators have been hampered due to the absence of knowledge on the intrinsic molecular aspects by which efflux occurs, namely the specific steps that correlates drug recognition, ATP binding and efflux-related conformational changes. Experimental evidences for these processes are also difficult to obtain and only provide small pieces of information that need to be assembled for better comprehension of a wider and complex process that is drug efflux. A promising alternative relies on cutting-edge computational techniques to provide new insights on key aspects that are determinant to understand how P-gp efflux can be effectively reversed. With the contribution of ligand-based or structure-based computational methods, P-gp drug efflux is slowly becoming a dynamic and reactive process rather than a simple response to drug binding, with the complex architecture of ABC transporters playing a determinant role not only in drug recognition but in the coordination of ATP-driven conformational changes that ultimately drives drug efflux. The major enlightenments that computational studies provided toward a better comprehension of MDR and P-gp efflux phenomena are hereby described.The demographic effect of this pathology on the general population, especially in the industrialized countries, is becoming severely affected by a rapid increase in the number of new cancers (Figure 1). It is estimated that by 2030 the number of new cases (excluding nonmelanoma skin cancer) will grow 32.8% (more than 21 million), with an estimated increase of 34.6% (1.3 million) in the total number of deaths. 2,3 Thus, new and improved chemotherapy regimens are needed to counterweight such predictions. However, cancer therapy evolution is directly related to a greater knowledge on the basic molecular mechanisms Volume 5, January/February 2015 Although the above structures contributed to a better comprehension of the ABC exporters' topology, a Volume 5, January/February 2015

show abstract

Section: Multidrug Resistance and Abc Transportersmentioning

confidence: 99%

Section: Multidrug Resistance and Abc Transportersmentioning

confidence: 99%

Section: Multidrug Resistance and Abc Transportersmentioning

confidence: 99%

See 1 more Smart Citation

Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

Ferreira

Santos

2014

WIREs Comput Mol Sci

View full text Add to dashboard Cite

show abstract

“…The development of multidrug resistance (MDR) is one major impediment in cancer and antibiotic therapies [1] – [3] . In 1976 Juliano and Ling were able to associate the occurrence of MDR with the presence of P-glycoprotein (P-gp), the most prominent member of the adenosine triphosphate (ATP) binding cassette (ABC) transporter superfamily [4] – [6] . ABC proteins are energy dependent transporters with P-gp (ABCB1), multidrug resistance protein 1 (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2) playing an important role in the protection of cells from harmful xenotoxins.…”

Section: Introductionmentioning

confidence: 99%

Exhaustive Sampling of Docking Poses Reveals Binding Hypotheses for Propafenone Type Inhibitors of P-Glycoprotein

2011

View full text Add to dashboard Cite

Overexpression of the xenotoxin transporter P-glycoprotein (P-gp) represents one major reason for the development of multidrug resistance (MDR), leading to the failure of antibiotic and cancer therapies. Inhibitors of P-gp have thus been advocated as promising candidates for overcoming the problem of MDR. However, due to lack of a high-resolution structure the concrete mode of interaction of both substrates and inhibitors is still not known. Therefore, structure-based design studies have to rely on protein homology models. In order to identify binding hypotheses for propafenone-type P-gp inhibitors, five different propafenone derivatives with known structure-activity relationship (SAR) pattern were docked into homology models of the apo and the nucleotide-bound conformation of the transporter. To circumvent the uncertainty of scoring functions, we exhaustively sampled the pose space and analyzed the poses by combining information retrieved from SAR studies with common scaffold clustering. The results suggest propafenone binding at the transmembrane helices 5, 6, 7 and 8 in both models, with the amino acid residue Y307 playing a crucial role. The identified binding site in the non-energized state is overlapping with, but not identical to, known binding areas of cyclic P-gp inhibitors and verapamil. These findings support the idea of several small binding sites forming one large binding cavity. Furthermore, the binding hypotheses for both catalytic states were analyzed and showed only small differences in their protein-ligand interaction fingerprints, which indicates only small movements of the ligand during the catalytic cycle.

show abstract

“…Pglycoprotein (P-gp/ABCB1), is the model cell membrane ABC transporter 50,51 where high P-gp inhibitory potency has been associated with high lipophilicity and an interaction with the transporter via the membrane bilayer. 52,53 The direct exposure of the compound to motile L. donovani, extracellular promastigote stage parasites, in vitro, showed no inhibitory activity over a 2h period indicating that active uptake of the peptide did not occur due to differences in feeding between the extracellular promastigote and amastigote stages of these different parasites.…”

Section: 49mentioning

confidence: 99%

Antiprotozoal glutathione derivatives with flagellar membrane binding activity against T. brucei rhodesiense

Daunes

Yardley

Croft

et al. 2017

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

The ABC Transporters: Structural Insights into Drug Transport

Cited by 8 publications

References 226 publications

Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

Exhaustive Sampling of Docking Poses Reveals Binding Hypotheses for Propafenone Type Inhibitors of P-Glycoprotein

Antiprotozoal glutathione derivatives with flagellar membrane binding activity against T. brucei rhodesiense

Contact Info

Product

Resources

About