Modeling Substrate Entry into the P-Glycoprotein Efflux Pump at the Blood–Brain Barrier

Jorgensen, Christian; Ulmschneider, Martin B.; Searson, Peter C.

doi:10.1021/acs.jmedchem.3c01069

Cited by 3 publications

(1 citation statement)

References 76 publications

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“…We initiated simulations from two different setups, as a long dynamic loop connecting the N- and C-terminal domains spanning residues 631 to 693 was not resolved in the experimental structure, and we decided to test its effect upon ligand binding. In the first setup, we reconstructed this loop, modelling it using the program GalaxyFill 74 as described in a previous study 75 . For comparison in an alternative setup, the loop was not reconstructed, and instead, the termini of residues 630 and 694 were terminated using standard patching groups (truncated model).…”

Section: Methodsmentioning

confidence: 99%

Exploring bat-inspired cyclic tryptophan diketopiperazines as ABCB1 Inhibitors

Koh,

Itahana,

Krah

et al. 2024

Commun Chem

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Chemotherapy-induced drug resistance remains a major cause of cancer recurrence and patient mortality. ATP binding cassette subfamily B member 1 (ABCB1) transporter overexpression in tumors contributes to resistance, yet current ABCB1 inhibitors have been unsuccessful in clinical trials. To address this challenge, we propose a new strategy using tryptophan as a lead molecule for developing ABCB1 inhibitors. Our idea stems from our studies on bat cells, as bats have low cancer incidences and high ABCB1 expression. We hypothesized that potential ABCB1 substrates in bats could act as competitive inhibitors in humans. By molecular simulations of ABCB1-substrate interactions, we generated a benzylated Cyclo-tryptophan (C3N-Dbn-Trp2) that inhibits ABCB1 activity with efficacy comparable to or better than the classical inhibitor, verapamil. C3N-Dbn-Trp2 restored chemotherapy sensitivity in drug-resistant human cancer cells with no adverse effect on cell proliferation. Our unique approach presents a promising lead toward developing effective ABCB1 inhibitors to treat drug-resistant cancers.

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Section: Methodsmentioning

confidence: 99%

Exploring bat-inspired cyclic tryptophan diketopiperazines as ABCB1 Inhibitors

Koh,

Itahana,

Krah

et al. 2024

Commun Chem

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Coupling the role of lipids to the conformational dynamics of the ABC transporter P-glycoprotein

De Vecchis,

Schäfer

2024

Biophysical Journal

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Coupling the role of lipids to the conformational dynamics of the ABC transporter P-gp

Vecchis,

Schäfer

2024

Preprint

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The ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) is a multidrug efflux pump that is overexpressed in a variety of cancers and associated with the drug resistance phenomenon. P-gp structures were previously determined in detergent and in nanodiscs, in which different transmembrane helix conformations were found, "straight" and "kinked", respectively, indicating a possible role of the lipid environment on the P-gp structural ensemble. Here, we investigate the dynamic conformational ensembles and protein-lipid interactions of the two human P-gp inward-open conformers (straight and kinked) employing all-atom molecular dynamics simulations in asymmetric multicomponent lipid bilayers that mimic the highly specialized hepatocyte membrane in which P-gp is expressed. The two conformers are found to differ in terms of the accessibility of the substrate cavity. The MD simulations show how cholesterol and different lipid species wedge, snorkel, and partially enter within the cavity of the straight P-gp conformer solved in detergent. However, the access to the cavity of kinked P-gp conformer solved in nanodiscs is restricted. Furthermore, the volume and dynamic fluctuations of the substrate cavity largely differ between the two P-gp structures, and are modulated by the presence (or absence) of cholesterol in the membrane and/or of ATP. From the mechanistic perspective, our findings indicate that the straight conformer likely precedes the kinked conformer in the functional working cycle of P-pg, with the latter conformation representing a post substrate-bound state. The inaccessibility of the main transmembrane cavity in the kinked conformer might be crucial in preventing substrate disengagement and transport withdrawal. Remarkably, in our unbiased MD simulations, one transmembrane portal helix (TM10) of the straight conformer underwent a spontaneous conformational transition to a kinked conformation, underlining the relevance of both conformations in a native phospholipid environment and revealing structural descriptors defining the transition between two P-gp conformers.

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Modeling Substrate Entry into the P-Glycoprotein Efflux Pump at the Blood–Brain Barrier

Cited by 3 publications

References 76 publications

Exploring bat-inspired cyclic tryptophan diketopiperazines as ABCB1 Inhibitors

Exploring bat-inspired cyclic tryptophan diketopiperazines as ABCB1 Inhibitors

Coupling the role of lipids to the conformational dynamics of the ABC transporter P-glycoprotein

Coupling the role of lipids to the conformational dynamics of the ABC transporter P-gp

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