Identification of Possible Binding Sites for Morphine and Nicardipine on the Multidrug Transporter P-Glycoprotein Using Umbrella Sampling Techniques

Subramanian, Nandhitha; Čondić‐Jurkić, Karmen; Mark, Alan E.; O’Mara, Megan L.

doi:10.1021/ci5007382

Cited by 30 publications

(56 citation statements)

References 89 publications

(252 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This strategy has provided insight into the spatial separation of drug interaction sites on P-gp. Several mutagenesis and structural studies suggested that specific drugs bound within the central cavity of the TMD [19,20,28,29,33]. However, in the present investigation, three of the four drug binding sites had contact residues located at the lipid-protein interface and outside the central cavity.…”

Section: Discussioncontrasting

confidence: 68%

“…The candidate residues identified using this approach were in broad agreement with those identified from docking and MD simulation based studies [20,34,35]. Another investigation using a large number of P-gp isoforms adopted a different approach using arginine enhancer mutations to identify residues within the translocation pathway [36].…”

Section: Discussionsupporting

confidence: 64%

“…The residue has also been widely implicated to reside within the translocation pore for a number of drugs (e.g. tariquidar, verapamil, doxorubicin, morphine) [20,36,41]. Furthermore, residues proximal to F978 (A980), and within the central cavity (F343), have been shown by EPR-spectroscopy to undergo a shift in accessibility to a polar environment as P-gp switches between conformations in the transport process [42].…”

Section: Discussionmentioning

confidence: 99%

“…Structural models of mouse P-gp suggested that the central cavity of the protein was the likely region for drug binding [19,20]. Moreover, the central cavity is lined by a number of TM helices that have been widely implicated in the interaction of drugs with P-gp during the translocation process [12,16,21].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Location of contact residues in pharmacologically distinct drug binding sites on P-glycoprotein

Mittra

Pavy

Subramanian

et al. 2017

Biochemical Pharmacology

View full text Add to dashboard Cite

The multidrug resistance P-glycoprotein (P-gp) is characterised by the ability to bind and/or transport an astonishing array of drugs. This poly-specificity is imparted by at least four pharmacologically distinct binding sites within the transmembrane domain. Whether or not these sites are spatially distinct has remained unclear. Biochemical and structural investigations have implicated a central cavity as the likely location for the binding sites. In the present investigation, a number of contact residues that are involved in drug binding were identified through biochemical assays using purified, reconstituted P-gp. Drugs were selected to represent each of the four pharmacologically distinct sites. Contact residues important in rhodamine123 binding were identified in the central cavity of P-gp. However, contact residues for the binding of vinblastine, paclitaxel and nicardipine were located at the lipid-protein interface rather than the central cavity. A key residue (F978) within the central cavity is believed to be involved in coupling drug binding to nucleotide hydrolysis. Data observed in this investigation suggest the presence of spatially distinct drug binding sites connecting through to a single translocation pore in the central cavity.

show abstract

Section: Discussioncontrasting

confidence: 68%

Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Location of contact residues in pharmacologically distinct drug binding sites on P-glycoprotein

Mittra

Pavy

Subramanian

et al. 2017

Biochemical Pharmacology

View full text Add to dashboard Cite

show abstract

“…They also concluded that mouse P-gp and Sav1866 might employ slightly different transport mechanisms, especially with respect to the role of water. More recently, O'Mara and colleagues [45] investigated potential of mean force (PMF) profiles for morphine and nicardipine and showed that they bind at different but overlapping sites within the central transmembrane cavity.…”

Section: Based On Sav1866 To Obtain Structures Of Intermediate Statesmentioning

confidence: 99%

Homology modelling of human P-glycoprotein

Domicevica

Biggin

2015

Biochemical Society Transactions

View full text Add to dashboard Cite

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.

show abstract

Atomistic molecular dynamics simulations of ATP‐binding cassette transporters

Liu

et al. 2016

WIREs Comput Mol Sci

View full text Add to dashboard Cite

Membrane transporters are transmembrane proteins that facilitate the translocation of a broad range of substrates across biological membranes. These proteins play a pivotal role in drug absorption, distribution, metabolism, and excretion, as well as drug resistance in cancer and pathogenic microorganisms. Moreover, some of them are appealing therapeutic targets. Computational methods, especially atomistic molecular dynamics (MD) simulations, are now increasingly employed to investigate the structural and thermodynamic properties of these proteins. Computer simulations at an atomic resolution help to decipher the underlying mechanisms of these transporters and provide valuable insights into structure-based drug discovery. Here, recent advances of the applications of MD simulations on the studies of a major class of membrane transporters, the ATP-binding cassette (ABC) superfamily, are reviewed. The studies surveyed here are mainly focused on the working mechanisms of ABC transporters, including binding of substrates, conformational coupling between nucleotidebinding domains (NBDs) and transmembrane domains, dynamics of NBDs, and global movement of complete transporters. In addition, structural and functional changes upon mutations are also discussed in some medically relevant cases.

show abstract

Identification of Possible Binding Sites for Morphine and Nicardipine on the Multidrug Transporter P-Glycoprotein Using Umbrella Sampling Techniques

Cited by 30 publications

References 89 publications

Location of contact residues in pharmacologically distinct drug binding sites on P-glycoprotein

Location of contact residues in pharmacologically distinct drug binding sites on P-glycoprotein

Homology modelling of human P-glycoprotein

Atomistic molecular dynamics simulations of ATP‐binding cassette transporters

Contact Info

Product

Resources

About