scholarly journals Data-driven homology modelling of P-glycoprotein in the ATP-bound state indicates flexibility of the transmembrane domains

FEBS Journal ◽  
2009 ◽  
Vol 276 (4) ◽  
pp. 964-972 ◽  
Author(s):  
Thomas Stockner ◽  
Sjoerd J. de Vries ◽  
Alexandre M. J. J. Bonvin ◽  
Gerhard F. Ecker ◽  
Peter Chiba
Keyword(s):  
Homology Modelling ◽  
Bound State ◽  
Transmembrane Domains ◽  
Data Driven ◽  
P Glycoprotein

scholarly journals Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux

2006 ◽  
Vol 50 (9) ◽  
pp. 3102-3110 ◽  
Author(s):  
José M. Pérez-Victoria ◽  
Fernando Cortés-Selva ◽  
Adriana Parodi-Talice ◽  
Boris I. Bavchvarov ◽  
F. Javier Pérez-Victoria ◽  
...  
Keyword(s):  
Active Drug ◽  
Transmembrane Domains ◽  
Drug Efflux ◽  
Binding Domains ◽  
Mammalian Cell Lines ◽  
Structure Activity ◽  
P Glycoprotein ◽  
Leishmania Spp ◽  
Orally Active ◽  
Glycoprotein Inhibitors

ABSTRACT Miltefosine (hexadecylphosphocholine) is the first orally active drug approved for the treatment of leishmaniasis. We have previously shown the involvement of LtrMDR1, a P-glycoprotein-like transporter belonging to the ATP-binding cassette superfamily, in miltefosine resistance in Leishmania. Here we show that overexpression of LtrMDR1 increases miltefosine efflux, leading to a decrease in drug accumulation in the parasites. Although LtrMDR1 modulation might be an efficient way to overcome this resistance, a main drawback associated with the use of P-glycoprotein inhibitors is related to their intrinsic toxicity. In order to diminish possible side effects, we have combined suboptimal doses of modulators targeting both the cytosolic and transmembrane domains of LtrMDR1. Preliminary structure-activity relationships have allowed us to design a new and potent flavonoid derivative with high affinity for the cytosolic nucleotide-binding domains. As modulators directed to the transmembrane domains, we have selected one of the most potent dihydro-β-agarofuran sesquiterpenes described, and we have also studied the effects of two of the most promising, latest-developed modulators of human P-glycoprotein, zosuquidar (LY335979) and elacridar (GF120918). The results show that this combinatorial strategy efficiently overcomes P-glycoprotein-mediated parasite miltefosine resistance by increasing intracellular miltefosine accumulation without any side effect in the parental, sensitive, Leishmania line and in different mammalian cell lines.

scholarly journals Homology modelling of human P-glycoprotein

2015 ◽  
Vol 43 (5) ◽  
pp. 952-958 ◽  
Author(s):  
Laura Domicevica ◽  
Philip C. Biggin
Keyword(s):  
Structural Biology ◽  
Conformational Changes ◽  
Homology Modelling ◽  
Md Simulations ◽  
Multi Drug Resistance ◽  
Glycoprotein P ◽  
The Past ◽  
Atp Binding Cassette Transporter ◽  
P Glycoprotein ◽  
Great Progress

P-glycoprotein (P-gp) is an ATP-binding cassette transporter that exports a huge range of compounds out of cells and is thus one of the key proteins in conferring multi-drug resistance in cancer. Understanding how it achieves such a broad specificity and the series of conformational changes that allow export to occur form major, on-going, research objectives around the world. Much of our knowledge to date has been derived from mutagenesis and assay data. However, in recent years, there has also been great progress in structural biology and although the structure of human P-gp has not yet been solved, there are now a handful of related structures on which homology models can be built to aid in the interpretation of the vast amount of experimental data that currently exists. Many models for P-gp have been built with this aim, but the situation is complicated by the apparent flexibility of the system and by the fact that although many potential templates exist, there is large variation in the conformational state in which they have been crystallized. In this review, we summarize how homology modelling has been used in the past, how models are typically selected and finally illustrate how MD simulations can be used as a means to give more confidence about models that have been generated via this approach.

scholarly journals Does human P-glycoprotein efflux involve transmembrane alpha helix breakage?

2019 ◽  
Author(s):  
Cátia A. Bonito ◽  
Maria-José U. Ferreira ◽  
Ricardo J. Ferreira ◽  
Daniel J. V. A. dos Santos
Keyword(s):  
Recent Article ◽  
Alpha Helix ◽  
Transmembrane Domains ◽  
Lateral Compression ◽  
P Glycoprotein ◽  
Gate Region

AbstractThe occluded conformation suggested in a recent article that revealed a new inward-facing conformation for the human P-glycoprotein may not represent the closing of a gate region but instead an artifact derived from lateral compression in a too small sized nanodisc, used to stabilize the transmembrane domains of the transporter.

CRYO-Electron Microscopy of the Acto-Myosin-ATP Complex

1990 ◽  
Vol 48 (1) ◽  
pp. 248-249
Author(s):  
John Trinickt ◽  
Howard White
Keyword(s):  
Electron Microscopy ◽  
Atp Hydrolysis ◽  
Myosin Head ◽  
Bound State ◽  
Cross Linking ◽  
Weakly Bound ◽  
Cryo Electron Microscopy ◽  
Myosin Subfragment 1 ◽  
Attached State ◽  
High Fraction

The primary force of muscle contraction is thought to involve a change in the myosin head whilst attached to actin, the energy coming from ATP hydrolysis. This change in attached state could either be a conformational change in the head or an alteration in the binding angle made with actin. A considerable amount is known about one bound state, the so-called strongly attached state, which occurs in the presence of ADP or in the absence of nucleotide. In this state, which probably corresponds to the last attached state of the force-producing cycle, the angle between the long axis myosin head and the actin filament is roughly 45°. Details of other attached states before and during power production have been difficult to obtain because, even at very high protein concentration, the complex is almost completely dissociated by ATP. Electron micrographs of the complex in the presence of ATP have therefore been obtained only after chemically cross-linking myosin subfragment-1 (S1) to actin filaments to prevent dissociation. But it is unclear then whether the variability in attachment angle observed is due merely to the cross-link acting as a hinge.We have recently found low ionic-strength conditions under which, without resorting to cross-linking, a high fraction of S1 is bound to actin during steady state ATP hydrolysis. The structure of this complex is being studied by cryo-electron microscopy of hydrated specimens. Most advantages of frozen specimens over ambient temperature methods such as negative staining have already been documented. These include improved preservation and fixation rates and the ability to observe protein directly rather than a surrounding stain envelope. In the present experiments, hydrated specimens have the additional benefit that it is feasible to use protein concentrations roughly two orders of magnitude higher than in conventional specimens, thereby reducing dissociation of weakly bound complexes.

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