Cinnamophilin overcomes cancer multi-drug resistance via allosterically modulating human P-glycoprotein on both drug binding sites and ATPase binding sites

AbstractP-glycoprotein (ABCB1) is a ATP-binding cassette transporter that plays an important role in the removal of drugs and xenobiotic compounds from the cell. It is also associated with multi-drug resistance in cancer. Here we report novel features of the cryo-EM-derived structure of P-glycoprotein in the post-hydrolytic state: The cytosolic nucleotide-binding domains (NBDs) are separated despite ADP remaining bound to the NBDs. Gaps in the TMDs that connect to the inner hydrophilic cavity are back-filled by detergent head-groups from the annular detergent micelle and are close to two regions predicted to delineate two pseudo-symmetry-related drug-binding sites. In this conformation, the (newly-resolved) N-terminal extension, NBD-TMD linker region and gap-filling detergents all appear to impede NBD dimerisation. We propose a model for the mechanism of action of the exporter where ATP will be bound to the protein for most of the time, consistent with the high physiological ATP concentrationsin vivo.

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Atomic modelling and systematic mutagenesis identify residues in multiple drug binding sites that are essential for drug resistance in the major Candida transporter Cdr1

Biochimica et Biophysica Acta (BBA) - Biomembranes ◽

10.1016/j.bbamem.2016.08.011 ◽

2016 ◽

Vol 1858 (11) ◽

pp. 2858-2870 ◽

Cited By ~ 12

Author(s):

Shweta Nim ◽

Lucia Gonzalez Lobato ◽

Alexis Moreno ◽

Vincent Chaptal ◽

Manpreet Kaur Rawal ◽

...

Keyword(s):

Drug Resistance ◽

Binding Sites ◽

Drug Binding ◽

Multiple Drug ◽

Drug Binding Sites

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Computational Pharmacogenetics of P-Glycoprotein Mediated Antiepileptic Drug Resistance

The Open Bioinformatics Journal ◽

10.2174/1875036201811010197 ◽

2018 ◽

Vol 11 (1) ◽

pp. 197-207 ◽

Cited By ~ 2

Author(s):

Sindhu Varghese ◽

Ashok Palaniappan

Keyword(s):

Drug Resistance ◽

Treatment Failure ◽

Conformational Changes ◽

Binding Sites ◽

Docking Studies ◽

Drug Binding ◽

Experimental Investigations ◽

Binding Affinities ◽

Drug Binding Site ◽

P Glycoprotein

Background:The treatment of epilepsy using antiepileptogenic drugs is complicated by drug resistance, resulting in treatment failure in more than one-third of cases. Human P-glycoprotein (hPGP;MDR1) is a known epileptogenic mediator.Methods:Given that experimental investigations have suggested a role for pharmacogenetics in this treatment failure, it would be of interest to study hPGP polymorphisms that might contribute to the emergence of drug resistance. Changes in protein functional activity could result from mutations as well as altered abundance. Bioinformatics approaches were used to assess and rank the functional impact of 20 missenseMDR1polymorphisms and the top five were selected. The structures of the wildtype and variant hPGP were modelled based on the mouse PGP structure. Docking studies of the wildtype and variant hPGP with four standard anti-epileptic drugs were carried out.Results:Our results revealed that the drug binding site with respect to the wildtype protein was uniform. However, the variant hPGP proteins displayed a repertoire of binding sites with stronger binding affinities towards the drug.Conclusion:Our studies indicated that specific polymorphisms inMDR1could drive conformational changes of PGP structure, facilitating altered contacts with drug-substrates and thus modifying their bioavailability. This suggests thatMDR1polymorphisms could actively contribute to the emergence of pharmaco-resistance in antiepileptic therapy.

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