New light on multidrug binding by an ATP-binding-cassette transporter

Shilling, Richard A.; Venter, Henrietta; Velamakanni, Saroj; Bapna, Akanksha; Woebking, Barbara; Shahi, Sanjay; Veen, Hendrik W. van

doi:10.1016/j.tips.2006.02.008

Cited by 56 publications

(46 citation statements)

References 69 publications

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“…It is noteworthy that the amino acids in the intracellular loops and the transmembrane domains of the BCRP protein contain a large number of aromatic and hydrogen bond donor side chains (Doyle et al, 1998), complementary to the molecular features in the models developed in this study. The same situation has been observed in the substrate binding regions of P-gp (Seelig, 1998;Omote and Al-Shawi, 2006;Shilling et al, 2006), and this similarity could well contribute to the overlapping substrate specificity of the two transporters. So far, the low resolution of the crystal structures of human ABC transporters precludes direct examination of their drug binding sites (Rosenberg et al, 2005;McDevitt et al, 2006).…”

Section: Tablesupporting

confidence: 64%

A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2)

Matsson

Englund²,

Ahlin³

et al. 2007

J Pharmacol Exp Ther

111

103

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In this article, we explore the entire structural space of registered drugs to obtain a global model for the inhibition of the drug efflux transporter breast cancer resistance protein (BCRP; ABCG2). For this purpose, the inhibitory effect of 123 structurally diverse drugs and drug-like compounds on mitoxantrone efflux was studied in Saos-2 cells transfected with human wild-type (Arg482) BCRP. The search for BCRP inhibitors throughout the drug-like chemical space resulted in the identification of 29 previously unknown inhibitors. The frequency of BCRP inhibition was 3 times higher for compounds reported to interact with other ATP-binding cassette (ABC) transporters than for compounds without reported ABC transporter affinity.An easily interpreted computational model capable of discriminating inhibitors from noninhibitors using only two molecular descriptors, octanol-water partition coefficient at pH 7.4 and molecular polarizability, was constructed. The discriminating power of this two-descriptor model was 93% for the training set and 79% for the test set, respectively. The results were supported by a global pharmacophore model and are in agreement with a two-step mechanism for the inhibition of BCRP, where both the drug's capacity to insert into the cell membrane and to interact with the inhibitory binding site of the transporter are important.The ATP-binding cassette (ABC) transporter breast cancer resistance protein (BCRP; ABCG2) has received much attention for its role in resistance to various cytotoxic agents (Doyle et al., 1998;Krishnamurthy and Schuetz, 2006) and has recently been shown to also influence the disposition of structurally unrelated drugs from other therapeutic classes (Gupta et al., 2004;Jonker et al., 2005;Zhang et al., 2005). BCRP is expressed in many tissue barriers throughout the body, including the intestine, the blood-brain barrier, the blood-placenta barrier, and the liver canalicular membrane (Maliepaard et al., 2001;Fetsch et al., 2006). A picture is emerging that, similar to the most well studied ABC transporter, P-glycoprotein (ABCB1), BCRP interacts with a wide variety of compounds, and it is one of the major ABC transporters affecting drug disposition throughout the body. The key role of BCRP in drug disposition was recently exemplified by a 111 times higher systemic exposure to the antiinflammatory drug sulfasalazine after oral administration to Bcrp1-knockout mice compared with wild-type mice (Zaher et al., 2006). Furthermore, the human oral bioavailability of the BCRP substrate topotecan was more than doubled after coadministration with the potent inhibitor GF120918 (Elacridar) (Kruijtzer et al., 2002), highlighting the risk of significantly altered drug exposure due to inhibition of BCRP. It would therefore be of great interest to develop models that can predict drug-mediated BCRP inhibition, but so far, studies have been limited to structurally homologous series of compounds (Gupta et al., 2004), and the only published computational model was not validated with an ex...

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Section: Tablesupporting

confidence: 64%

A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2)

Matsson

Englund²,

Ahlin³

et al. 2007

J Pharmacol Exp Ther

111

103

View full text Add to dashboard Cite

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“…ABCB1 ⁄ P-gp, ABCC1 ⁄ MRP1, ABCC2 ⁄ MRP2, ABCC3 ⁄ MRP3 and ABCG2 ⁄ BCRP can transport an array of structurally distinct anti-cancer drugs, and their over-expression cause MDR [1,117]. MDR is a major hindrance for the success of clinical chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Phenotype Prediction of Non‐Synonymous Single‐Nucleotide Polymorphisms in Human ATP‐Binding Cassette Transporter Genes

Wang

Liu

Meng

et al. 2010

Basic Clin Pharma Tox

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A large number of non-synonymous single-nucleotide polymorphisms (nsSNPs) have been found in human genome, but there is poor knowledge on the relationship between the genotype and phenotype of these nsSNPs. Human ATP-binding cassette (ABC) transporters are able to transport a number of important substrates including endogenous and exogenous compounds. This study aimed to predict the phenotypical impact of nsSNPs of human ABC transporter genes, and the predicted results were further validated by reported phenotypical data from site-directed mutagenesis and clinical genetic studies. One thousand and six hundred thirty-two nsSNPs were found from 49 human ABC transporter genes. Using the PolyPhen and SIFT algorithms, 41.8-53.6% of nsSNPs in ABC transporter genes were predicted to have an impact on protein function. The prediction accuracy was up to 63-85% when compared with known phenotypical data from in vivo and in vitro studies. There was a significant concordance between the prediction results using SIFT and PolyPhen. Of nsSNPs predicted as deleterious, the prediction scores by SIFT and PolyPhen were significantly related to the number of nsSNPs with known phenotypes confirmed by experimental and human studies. The amino acid substitution variants are supposed to be the pathogenetic basis of increased susceptibility to certain diseases with Mendelian or complex inheritance, altered drug resistance and altered drug clearance and response. Predicting the phenotypic consequence of nsSNPs using computational algorithms may provide a better understanding of genetic differences in susceptibility to diseases and drug response. The prediction of nsSNPs in human ABC transporter genes would be useful hints for further genotype-phenotype studies.

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“…Transmembrane localization of P-gp residues involved in substrate recognition P-gp residues identified from point mutagenesis, chemical labeling (10,57), or crystallographic data (22). The equivalent residues belonging to MsbA, Sav1866, and SUR1 are identified thanks to the primary sequences alignment represented in supplemental Fig.S2.…”

Section: Tablementioning

confidence: 99%

“…This is reinforced by the close structural resemblance of SR47063 with rhodamine 123, a compound for which recognition by P-gp has been determined to be competitive with verapamil 9 and to correspond to pharmacophore I. 10 Due to the incomplete overlap with verapamil, SR47063 could sterically interfere with vinblastine, but this is difficult to ascertain experimentally. Fig.…”

Section: P-gpmentioning

confidence: 99%

“…Indeed, SUR is the target of a panel of structurally unrelated ligands, like P-gp and other multidrug transporters. Multispecific drug recognition by P-gp is still a misunderstood molecular property despite a mass of published data, including extensive mutational analyses (10) as well as a pharmacophore model of some of its known ligands (11). Because binding of SUR ligands has also been linked to some particular residues (12,13), it is of interest to compare the ligand recognition features of these two ABC proteins, with the aim of gaining new insights into both of them.…”

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confidence: 99%

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Recognition of Sulfonylurea Receptor (ABCC8/9) Ligands by the Multidrug Resistance Transporter P-glycoprotein (ABCB1)

Bessadok

Garcia

Jacquet

et al. 2011

Journal of Biological Chemistry

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ATP-sensitive K؉ (K ATP ) channels are the target of a number of pharmacological agents, blockers like hypoglycemic sulfonylureas and openers like the hypotensive cromakalim and diazoxide. These agents act on the channel regulatory subunit, the sulfonylurea receptor (SUR), which is an ABC protein with homologies to P-glycoprotein (P-gp). P-gp is a multidrug transporter expressed in tumor cells and in some healthy tissues. Because these two ABC proteins both exhibit multispecific recognition properties, we have tested whether SUR ligands could be substrates of P-gp. Interaction with P-gp was assayed by monitoring ATPase activity of P-gp-enriched vesicles. The blockers glibenclamide, tolbutamide, and meglitinide increased ATPase activity, with a rank order of potencies that correlated with their capacity to block K ATP channels. P-gp ATPase activity was also increased by the openers SR47063 (a cromakalim analog), P1075 (a pinacidil analog), and diazoxide. Thus, these molecules bind to P-gp (although with lower affinities than for SUR) and are possibly transported by P-gp. Competition experiments among these molecules as well as with typical P-gp substrates revealed a structural similarity between drug binding domains in the two proteins. To rationalize the observed data, we addressed the molecular features of these proteins and compared structural models, computerized by homology from the recently solved structures of murine P-gp and bacterial ABC transporters MsbA and Sav1866. Considering the various residues experimentally assigned to be involved in drug binding, we uncovered several hot spots, which organized spatially in two main binding domains, selective for SR47063 and for glibenclamide, in matching regions of both P-gp and SUR.ABC 8 proteins form a large superfamily of mostly membrane proteins. They present as common characteristics a nucleotide binding domain able to hydrolyze ATP, which includes the sequence motifs Walker A and B and the signature C (1). As membrane active transporters, they are expressed in virtually all branches of the living reign, and they exhibit a very broad diversity of transported substrates, handled in either the direction of influx or efflux (2). In higher mammals, they are involved in various pathophysiological situations and genetic diseases (3).The K ATP channel results from the constitutive association of four pore-forming Kir6.x subunits and four regulatory SUR subunits (4, 5). In various combinations of the SUR isoforms, SUR1, SUR2A, and SUR2B, and the Kir6 isoforms, Kir6.1 and Kir6.2, these channels are present in most excitable cells, including neuronal, cardiac muscle, smooth muscle, and endocrine cells (6), where they serve to couple membrane electrical properties to intracellular metabolism.SUR, a member of the ABCC/MRP (multidrug resistanceassociated protein) subfamily of ABC proteins, is the site of action of numerous drugs that cause either closing (K ATP channel blockers) or opening (K ATP channel openers) of the Kir6.x potassium pore (7). Blockers include antidi...

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New light on multidrug binding by an ATP-binding-cassette transporter

Cited by 56 publications

References 69 publications

A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2)

A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2)

Phenotype Prediction of Non‐Synonymous Single‐Nucleotide Polymorphisms in Human ATP‐Binding Cassette Transporter Genes

Recognition of Sulfonylurea Receptor (ABCC8/9) Ligands by the Multidrug Resistance Transporter P-glycoprotein (ABCB1)

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