ABCG2: does resolving its structure elucidate the mechanism?

Kapoor, Parth; Horsey, Aaron J.; Cox, Megan H.; Kerr, Ian D.

doi:10.1042/bst20180145

Cited by 16 publications

(14 citation statements)

References 62 publications

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“…ABCG2 is also crucial in the pharmacokinetics of several compounds [1][2][3] which is highlighted by the fact that the US Food and Drug Administration and the European Medicines Agency list ABCG2 among the transporters to be investigated for pharmacokinetics and drug-drug interactions [4,5]. Experimental data showed that ABCG2 can handle substrates with a wide variety in size and polarity [2,6,7]. Uric acid is a small and amphiphilic physiological substrate [8,9], Hoechts 33342 [10] is a large hydrophobic molecule, and methotrexate [11] or various sulfated and glucuronide conjugates [12] are more polar substrates.…”

Section: Introductionmentioning

confidence: 99%

The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations

Nagy

Tóth

Telbisz

et al. 2020

Cell. Mol. Life Sci.

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Atomic-level structural insight on the human ABCG2 membrane protein, a pharmacologically important transporter, has been recently revealed by several key papers. In spite of the wealth of structural data, the pathway of transmembrane movement for the large variety of structurally different ABCG2 substrates and the physiological lipid regulation of the transporter has not been elucidated. The complex molecular dynamics simulations presented here may provide a breakthrough in understanding the steps of the substrate transport process and its regulation by cholesterol. Our analysis revealed drug binding cavities other than the central binding site and delineated a putative dynamic transport pathway for substrates with variable structures. We found that membrane cholesterol accelerated drug transport by promoting the closure of cytoplasmic protein regions. Since ABCG2 is present in all major biological barriers and drug-metabolizing organs, influences the pharmacokinetics of numerous clinically applied drugs, and plays a key role in uric acid extrusion, this information may significantly promote a reliable prediction of clinically important substrate characteristics and drug-drug interactions.

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Section: Introductionmentioning

confidence: 99%

The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations

Nagy

Tóth

Telbisz

et al. 2020

Cell. Mol. Life Sci.

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“…Structural data on the ABCG family have brought us considerably further forwards in understanding the mechanism of these half-transporters [18,23]. Until there were structural data, the region between the NBD of ABCGs and the first transmembrane (TM) helix (over 150 residues in total, e.g., from ca.…”

Section: Discussionmentioning

confidence: 99%

“…These structures have revealed that ABCG2 has an internal cavity for drug substrate and inhibitors that is connected to an external cavity and that the propulsion of bound substrates from one cavity to the other is likely to form the basis for transmembrane transport [19][20][21]23]. The structures have already provided the foundation for understanding numerous studies that have identified specific residues of importance in contributing towards drug specificity and inter-domain communication [24][25][26], and will continue to help understand how drug binding and transport is coupled to nucleotide binding and hydrolysis [27].…”

Section: Introductionmentioning

confidence: 99%

Disruption of the Unique ABCG-Family NBD:NBD Interface Impacts Both Drug Transport and ATP Hydrolysis

Kapoor

Briggs

Cox

et al. 2020

IJMS

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ABCG2 is one of a triumvirate of human multidrug ATP binding cassette (ABC) transporters that are implicated in the defense of cells and tissues against cytotoxic chemicals, but these transporters can also confer chemotherapy resistance states in oncology. Understanding the mechanism of ABCG2 is thus imperative if we are to be able to counter its deleterious activity. The structure of ABCG2 and its related family members (ABCG5/G8) demonstrated that there were two interfaces between the nucleotide binding domains (NBD). In addition to the canonical ATP “sandwich-dimer” interface, there was a second contact region between residues at the C-terminus of the NBD. We investigated this second interface by making mutations to a series of residues that are in close interaction with the opposite NBD. Mutated ABCG2 isoforms were expressed in human embryonic kidney (HEK) 293T cells and analysed for targeting to the membrane, drug transport, and ATPase activity. Mutations to this second interface had a number of effects on ABCG2, including altered drug specificity, altered drug transport, and, in two mutants, a loss of ATPase activity. The results demonstrate that this region is particularly sensitive to mutation and can impact not only direct, local NBD events (i.e., ATP hydrolysis) but also the allosteric communication to the transmembrane domains and drug transport.

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“…Nonetheless, the fungal NBD1 has three minor differences, in that (i) a glutamine residue in the Q-loop is replaced with glutamate, (ii) the histidine residue in the H-loop is substituted with tyrosine and (iii) the Pro-loop is missing but contains a glycine instead [ 337 ] ( Table 4 ). The non-identical deviant NBDs in fungal PDRs [ 41 , 216 , 338 , 339 ] may support an asymmetric catalytic cycle as proposed for ABCG5/G8 [ 38 , 339 , 340 , 341 ], whereas “symmetric” cycles require the presence of fully conserved “canonical” ATP-binding sites in both NBDs.…”

Section: C Albicans Pdr/cdr1 Holds All Conserved Motifs Critical For Abcg Functionmentioning

confidence: 99%

Multidrug Resistance in Mammals and Fungi—From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms

Khunweeraphong

Kuchler

2021

IJMS

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Multidrug resistance (MDR) can be a serious complication for the treatment of cancer as well as for microbial and parasitic infections. Dysregulated overexpression of several members of the ATP-binding cassette transporter families have been intimately linked to MDR phenomena. Three paradigm ABC transporter members, ABCB1 (P-gp), ABCC1 (MRP1) and ABCG2 (BCRP) appear to act as brothers in arms in promoting or causing MDR in a variety of therapeutic cancer settings. However, their molecular mechanisms of action, the basis for their broad and overlapping substrate selectivity, remains ill-posed. The rapidly increasing numbers of high-resolution atomic structures from X-ray crystallography or cryo-EM of mammalian ABC multidrug transporters initiated a new era towards a better understanding of structure–function relationships, and for the dynamics and mechanisms driving their transport cycles. In addition, the atomic structures offered new evolutionary perspectives in cases where transport systems have been structurally conserved from bacteria to humans, including the pleiotropic drug resistance (PDR) family in fungal pathogens for which high resolution structures are as yet unavailable. In this review, we will focus the discussion on comparative mechanisms of mammalian ABCG and fungal PDR transporters, owing to their close evolutionary relationships. In fact, the atomic structures of ABCG2 offer excellent models for a better understanding of fungal PDR transporters. Based on comparative structural models of ABCG transporters and fungal PDRs, we propose closely related or even conserved catalytic cycles, thus offering new therapeutic perspectives for preventing MDR in infectious disease settings.

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ABCG2: does resolving its structure elucidate the mechanism?

Cited by 16 publications

References 62 publications

The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations

The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations

Disruption of the Unique ABCG-Family NBD:NBD Interface Impacts Both Drug Transport and ATP Hydrolysis

Multidrug Resistance in Mammals and Fungi—From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms

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