Gout, genetics and ABC transporters

Basseville, Agnès; Bates, Susan E.

doi:10.3410/b3-23

Cited by 22 publications

(23 citation statements)

References 36 publications

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“…The mutation Q141K is a reported single nucleotide polymorphism (SNP) of ABCG2 associated with hyperuricaemia and gout. It results in decreased expression or degradation of the protein, probably due to misfolding [47,48]. Our structure shows that Q141 is located in the NBD on an α-helix adjacent to TM1a of the TMD, where it can form a hydrogen bond with N158, confirming the previous in silico predictions ( Supplementary Fig.…”

Section: Insight Into the Nucleotide Binding Domainssupporting

confidence: 90%

Structural basis of small-molecule inhibition of human multidrug transporter ABCG2

Jackson

Manolaridis

Kowal

et al. 2018

Nat Struct Mol Biol

277

368

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ABCG2 is an ATP-binding cassette (ABC) transporter that protects tissues against xenobiotics, affects the pharmacokinetics of drugs and contributes to multidrug resistance. Although many inhibitors and modulators of ABCG2 have been developed, understanding their structure-activity relationship requires high-resolution structural insight. Here, we present cryo-EM structures of human ABCG2 bound to synthetic derivatives of the fumitremorgin C-related inhibitor Ko143 or the multidrug resistance modulator tariquidar. Both compounds are bound to the central, inward-facing cavity of ABCG2, blocking access for substrates and preventing conformational changes required for ATP hydrolysis. The high resolutions allowed for de novo building of the entire transporter and also revealed tightly bound phospholipids and cholesterol interacting with the lipid-exposed surface of the transmembrane domains (TMDs). Extensive chemical modifications of the Ko143 scaffold combined with in vitro functional analyses revealed the details of ABCG2 interactions with this compound family and provide a basis for the design of novel inhibitors and modulators.

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Section: Insight Into the Nucleotide Binding Domainssupporting

confidence: 90%

Structural basis of small-molecule inhibition of human multidrug transporter ABCG2

Jackson

Manolaridis

Kowal

et al. 2018

Nat Struct Mol Biol

277

368

View full text Add to dashboard Cite

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“…The transporter substrate mitoxantrone (MX) has also been shown to serve as a pharmacological chaperone for dimerization-deficient mutants which are normally impaired for trafficking to the cell surface 108 . Trafficking-deficient mutants have been further identified in regions of the protein not associated with dimerization, alterations which are genetically linked to gout 109 . Two additional transporters in the same gene family, ABCG5/8, form heterodimers involved in sterol secretion which have been reported to be downregulated at the cell surface in mouse models of leptin deficiency, a defect rescued by treatment with tauroursodeoxycholate 110 .…”

Section: Transportersmentioning

confidence: 99%

Inside job: ligand-receptor pharmacology beneath the plasma membrane

Babcock

2013

Acta Pharmacol Sin

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Most drugs acting on the cell surface receptors are membrane permeable and thus able to engage their target proteins in different subcellular compartments. However, these drugs' effects on cell surface receptors have historically been studied on the plasma membrane alone. Increasing evidence suggests that small molecules may also modulate their targeted receptors through membrane trafficking or organelle-localized signaling inside the cell. These additional modes of interaction have been reported for functionally diverse ligands of GPCRs, ion channels, and transporters. Such intracellular drug-target engagements affect cell surface expression. Concurrent intracellular and cell surface signaling may also increase the complexity and therapeutic opportunities of small molecule modulation. Here we discuss examples of ligand-receptor interactions that are present in both intra- and extracellular sites, and the potential therapeutic opportunities presented by this phenomenon.

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“…Uric acid is the final product of purine nucleoside metabolism by xanthine dehydrogenase (XDH, EC 1.17.1.4) in humans. Humans do not express urate oxidase (UOX, EC 1.7.3.3, uricase) that transforms uric acid to allantoin, a more soluble substance than uric acid [ 1 , 2 ]. The level of uric acid is well controlled mainly by the balance between production from purine nucleosides in liver and excretion into urine through kidneys [ 1 , 2 ].…”

Section: Introductionmentioning

confidence: 99%

Intestinal tract is an important organ for lowering serum uric acid in rats

Yin

Gao

et al. 2017

PLoS ONE

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The kidney was recognized as a dominant organ for uric acid excretion. The main aim of the study demonstrated intestinal tract was an even more important organ for serum uric acid (SUA) lowering. Sprague-Dawley rats were treated normally or with antibiotics, uric acid, adenine, or inosine of the same molar dose orally or intraperitoneally for 5 days. Rat’s intestinal tract was equally divided into 20 segments except the cecum. Uric acid in serum and intestinal segment juice was assayed. Total RNA in the initial intestinal tract and at the end ileum was extracted and sequenced. Protein expression of xanthine dehydrogenase (XDH) and urate oxidase (UOX) was tested by Western blot analysis. The effect of oral UOX in lowering SUA was investigated in model rats treated with adenine and an inhibitor of uric oxidase for 5 days. SUA in the normal rats was 20.93±6.98 μg/ml, and total uric acid in the intestinal juice was 308.27±16.37 μg, which is two times more than the total SUA. The uric acid was very low in stomach juice, and attained maximum in the juice of the first segment (duodenum) and then declined all the way till the intestinal end. The level of uric acid in the initial intestinal tissue was very high, where XDH and most of the proteins associated with bicarbonate secretion were up-regulated. In addition, SUA was decreased by oral UOX in model rats. The results suggested that intestinal juice was an important pool for uric acid, and intestinal tract was an important organ for SUA lowering. The uric acid distribution was associated with uric acid synthesis and secretion in the upper intestinal tract, and reclamation in the lower.

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Gout, genetics and ABC transporters

Cited by 22 publications

References 36 publications

Structural basis of small-molecule inhibition of human multidrug transporter ABCG2

Structural basis of small-molecule inhibition of human multidrug transporter ABCG2

Inside job: ligand-receptor pharmacology beneath the plasma membrane

Intestinal tract is an important organ for lowering serum uric acid in rats

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