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Exploration of the conformational landscape in pregnane X receptor reveals a new binding pocket

Chandran, Aneesh and Vishveshwara, Saraswathi (2016) Exploration of the conformational landscape in pregnane X receptor reveals a new binding pocket. In: PROTEIN SCIENCE, 25 (11). pp. 1989-2005.

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Official URL: http://dx.doi.org/10.1002/pro.3012


Ligand-regulated pregnane X receptor (PXR), a member of the nuclear receptor superfamily, plays a central role in xenobiotic metabolism. Despite its critical role in drug metabolism, PXR activation can lead to adverse drug-drug interactions and early stage metabolism of drugs. Activated PXR can induce cancer drug resistance and enhance the onset of malignancy. Since promiscuity in ligand binding makes it difficult to develop competitive inhibitors targeting PXR ligand binding pocket (LBP), it is essential to identify allosteric sites for effective PXR antagonism. Here, molecular dynamics (MD) simulation studies unravelled the existence of two different conformational states, namely ``expanded'' and ``contracted'', in apo PXR ligand binding domain (LBD). Ligand binding events shifted this conformational equilibrium and locked the LBD in a single ``ligand-adaptable'' conformational state. Ensemble-based computational solvent mapping identified a transiently open potential small molecule binding pocket between alpha 5 and alpha 8 helices, named ``alpha 8 pocket'', whose opening-closing mechanism directly correlated with the conformational shift in LBD. A virtual hit identified through structure-based virtual screening against a8 pocket locks the pocket in its open conformation. MD simulations further revealed that the presence of small molecule at allosteric site disrupts the LBD dynamics and locks the LBD in a ``tightly-contracted'' conformation. The molecular details provided here could guide new structural studies to understand PXR activation and antagonism.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 07 Dec 2016 05:55
Last Modified: 07 Dec 2016 05:55
URI: http://eprints.iisc.ac.in/id/eprint/55547

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