Impact of the Recent Mouse P‐Glycoprotein Structure for Structure‐Based Ligand Design

Klepsch, Freya; Ecker, Gerhard F.

doi:10.1002/minf.201000017

Cited by 24 publications

(24 citation statements)

References 95 publications

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“…One example is handling of the cyclic hexapeptides QZ59-RRR and QZ59-SSS, where the SSS enantiomer is a more potent inhibitor of mouse P-gp-mediated CAM efflux than the RRR enantiomer (30). This is presumably because SSS occupies two distinct binding sites in the drugbinding pocket whereas QZ59-RRR occupies only one (30,38,39).…”

Section: Abcg2 With Clear Apical Localization and Mdr-like Activitiesmentioning

confidence: 99%

Localization and Substrate Selectivity of Sea Urchin Multidrug (MDR) Efflux Transporters

Gökirmak

Campanale

Shipp

et al. 2012

Journal of Biological Chemistry

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Background: MDR transporters are important for many human diseases, but their phylogenetic origins and diversity are poorly understood. Results: Sea urchin MDR transporters homologous to ABCB1, ABCC1, and ABCG2 were characterized. Conclusion: Substitutions in TMH6 tune substrate selectivity of ABCB1 in sea urchins. Significance: Polyspecific MDR transport is conserved despite fine-tuning of substrate selectivity in different clades.

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Section: Abcg2 With Clear Apical Localization and Mdr-like Activitiesmentioning

confidence: 99%

Localization and Substrate Selectivity of Sea Urchin Multidrug (MDR) Efflux Transporters

Gökirmak

Campanale

Shipp

et al. 2012

Journal of Biological Chemistry

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“…The inward-facing conformation is able to bind drugs, because of its initial stage of the transport cycle (Kerr, Jones, & George, 2010). The internal cavity of P-gp is large for binding hydrophobic drugs with different orientations and at different locations (Tarcsay & Keseru, 2011), and meanwhile, two portals in the inner leaflet part of the protein allow the entry of hydrophobic drugs from the lipid bilayer (Hennessy & Spiers, 2007;Klepsch & Ecker, 2010;Sharom, 2008).…”

Section: Introductionmentioning

confidence: 99%

The flexibility of P-glycoprotein for its poly-specific drug binding from molecular dynamics simulations

Liu¹,

Hou²,

Feng³

et al. 2013

Journal of Biomolecular Structure and Dynamics

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The multidrug efflux pump P-glycoprotein (P-gp) contributes to multidrug resistance in about half of human cancers. Recently, high resolution X-ray crystal structures of mouse P-gp (inward-facing) were reported, which significantly facilitates the understanding of the function of P-gp and the structure-based design of inhibitors for P-gp. Here we perform 20 ns molecular dynamics simulations of inward-facing P-gp with/without ligand in explicit lipid and water to investigate the flexibility of P-gp for its poly-specific drug binding. By analyzing the interactions between P-gp and QZ59-RRR or QZ59-SSS, we summarize the important residues and the flexibility of different parts of P-gp. Particularly, the flexibility of the side chains of aromatic residues (Phe and Tyr) allows them to form rotamers with different orientations in the binding pocket, which plays a critical role for the poly-specificity of the drug-binding cavity of P-gp. MD simulations reveal that trans-membrane (TM) TM12 and TM6 are flexible and contribute to the poly-specific drug binding, while TM4 and TM5 are rigid and stabilize the whole structure. We also construct outward-facing P-gp based on the MsbA structure and perform 20 ns MD simulations. The comparison between the MD results for outward-facing P-gp and those for inward-facing P-gp shows that the TM parts in outward-facing P-gp undergo significant conformational change to facilitate the export of small molecules.

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“…32) We also constructed human P-gp models based on 2 complex structures and attempted the docking of methoxyfenozide to the protein models. Four possible poses were obtained and the interaction of each pose with P-gp was investigated.…”

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confidence: 99%

Substrate recognition by P-glycoprotein efflux transporters: Structure-ATPase activity relationship of diverse chemicals and agrochemicals

et al. 2013

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P-glycoprotein (P-gp) is a member of the ATP-binding cassette transporter family. It actively transports a wide variety of compounds out of cells and functions as an energy-dependent efflux pump to protect humans from xenobiotics. P-gp also plays an important role in multidrug resistance in the treatment of cancers. However, the mechanism of P-gp substrate recognition is complicated and still poorly understood. In this study, we screened diverse chemicals, especially agrochemicals by measuring the ATPase activity of human P-gp and found that several classes of chemicals including dibenzoylhydrazine (DBH) insecticides could be substrates of P-gp. ATPase activity was quantitatively analyzed using a 3D quantitative structure-activity relationship, comparative molecular field analysis (CoMFA), and the favorable and unfavorable properties of ligands for ATPase activity were clarified. We also performed a docking simulation of a DBH-type compound with P-gp to predict the binding mode, which was supported by the CoMFA results.

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Impact of the Recent Mouse P‐Glycoprotein Structure for Structure‐Based Ligand Design

Cited by 24 publications

References 95 publications

Localization and Substrate Selectivity of Sea Urchin Multidrug (MDR) Efflux Transporters

Localization and Substrate Selectivity of Sea Urchin Multidrug (MDR) Efflux Transporters

The flexibility of P-glycoprotein for its poly-specific drug binding from molecular dynamics simulations

Substrate recognition by P-glycoprotein efflux transporters: Structure-ATPase activity relationship of diverse chemicals and agrochemicals

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