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Tsuji M.,Institute of Molecular Function | Shudo K.,Japan Pharmaceutical Information Center | Kagechika H.,Tokyo Medical and Dental University
FEBS Open Bio | Year: 2017

Understanding and identifying the receptor subtype selectivity of a ligand is an important issue in the field of drug discovery. Using a combination of classical molecular mechanics and quantum mechanical calculations, this report assesses the receptor subtype selectivity for the human retinoid X receptor (hRXR) and retinoic acid receptor (hRAR) ligand-binding domains (LBDs) complexed with retinoid ligands. The calculated energies show good correlation with the experimentally reported binding affinities. The technique proposed here is a promising method as it reveals the origin of the receptor subtype selectivity of selective ligands. © 2016 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.


Tsuji M.,Institute of Molecular Function | Shudo K.,Japan Pharmaceutical Information Center | Kagechika H.,Tokyo Medical and Dental University
Journal of Computer-Aided Molecular Design | Year: 2015

Retinoid X receptors (RXRs) are ligand-controlled transcription factors which heterodimerize with other nuclear receptors to regulate gene transcriptions associated with crucial biological events. 9-cis retinoic acid (9cRA), which transactivates RXRs, is believed to be an endogenous RXR ligand. All-trans retinoic acid (ATRA) is a natural ligand for retinoic acid receptors (RARs), which heterodimerize with RXRs. Although the concentration of 9cRA in tissues is very low, ATRA is relatively abundant and some reports show that ATRA activates RXRs. We computationally studied the possibility of ATRA binding to RXRs using two different docking methods with our developed programs to assess the binding affinities of naturally occurring retinoids. The simulations showed good correlations to the reported binding affinities of these molecules for RXRs and RARs. © 2015 Springer International Publishing Switzerland


PubMed | Institute of Molecular Function, Japan Pharmaceutical Information Center and Tokyo Medical and Dental University
Type: Journal Article | Journal: Journal of computer-aided molecular design | Year: 2015

Retinoid X receptors (RXRs) are ligand-controlled transcription factors which heterodimerize with other nuclear receptors to regulate gene transcriptions associated with crucial biological events. 9-cis retinoic acid (9cRA), which transactivates RXRs, is believed to be an endogenous RXR ligand. All-trans retinoic acid (ATRA) is a natural ligand for retinoic acid receptors (RARs), which heterodimerize with RXRs. Although the concentration of 9cRA in tissues is very low, ATRA is relatively abundant and some reports show that ATRA activates RXRs. We computationally studied the possibility of ATRA binding to RXRs using two different docking methods with our developed programs to assess the binding affinities of naturally occurring retinoids. The simulations showed good correlations to the reported binding affinities of these molecules for RXRs and RARs.


Tsuji M.,Institute of Molecular Function
Journal of Structural Biology | Year: 2014

Structural and sequence alignment analyses have revealed the existence of class-dependent and -independent local motifs involved in the overall fold of the ligand-binding domain (LBD) in the nuclear receptor (NR) superfamily. Of these local motifs, three local motifs, i.e., AF-2 fixed motifs, were involved in the agonist conformation of the activation function-2 (AF-2) region of the LBD. Receptor-agonist interactions increased the stability of these AF-2 fixed motifs in the agonist conformation. In contrast, perturbation of the AF-2 fixed motifs by a ligand or another protein molecule led the AF-2 architecture to adopt an antagonist conformation. Knowledge of this process should provide us with novel insights into the 'agonism' and 'antagonism' of NRs. © 2013 Elsevier Inc.


Tsuji M.,University of Tokyo | Tsuji M.,Institute of Molecular Function
Asian Journal of Organic Chemistry | Year: 2015

Sterically unbiased bicyclic and tricyclic olefins were reacted with electrophiles to assess the π-facial stereoselectivity. The stereochemical preference of the reactions of these olefins with electrophiles is attributed to the HOMO, which is derived from the interaction between a higher-lying πorbital and particular lower-lying σorbitals. The selectivity of electrophilic reactions of these olefinic molecules is thought to be controlled by two types of HOMO, which are formed by a combination of different orbitals, depending on the geometrical conditions. A novel interpretation of orbital interactions enabled us to account for the facial selectivity in a unified manner. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Tsuji M.,Institute of Molecular Function
Journal of Molecular Graphics and Modelling | Year: 2015

We successfully simulated receptor-ligand complex holo-form formation using the human retinoid X receptor-α ligand-binding domain (LBD) and its natural ligand, 9-cis retinoic acid. The success of this simulation was strongly dependent on the findings for an initial structure between the apo-LBD and the ligand as well as the discovery of the driving forces underlying the ligand-trapping and subsequent ligand-induction processes. Here, we would like to propose the "helix H3 three-point initial-binding hypothesis," which was instrumental in simulating the nuclear receptor (NR) superfamily. Using this hypothesis, we also succeeded in simulating holo-form formation of the human retinoic acid receptor-γ LBD and its natural ligand, all-trans retinoic acid. It is hoped that this hypothesis will facilitate novel understanding of both the ligand-trapping mechanism and the simultaneous C-terminal folding process in NR LBDs, as well as provide a new approach to drug design using a structure-based perspective. © 2015 Elsevier Inc. All rights reserved.


PubMed | Institute of Molecular Function
Type: | Journal: Journal of molecular graphics & modelling | Year: 2015

We successfully simulated receptor-ligand complex holo-form formation using the human retinoid X receptor- ligand-binding domain (LBD) and its natural ligand, 9-cis retinoic acid. The success of this simulation was strongly dependent on the findings for an initial structure between the apo-LBD and the ligand as well as the discovery of the driving forces underlying the ligand-trapping and subsequent ligand-induction processes. Here, we would like to propose the helix H3 three-point initial-binding hypothesis, which was instrumental in simulating the nuclear receptor (NR) superfamily. Using this hypothesis, we also succeeded in simulating holo-form formation of the human retinoic acid receptor- LBD and its natural ligand, all-trans retinoic acid. It is hoped that this hypothesis will facilitate novel understanding of both the ligand-trapping mechanism and the simultaneous C-terminal folding process in NR LBDs, as well as provide a new approach to drug design using a structure-based perspective.


PubMed | Institute of Molecular Function
Type: Journal Article | Journal: Journal of structural biology | Year: 2014

Structural and sequence alignment analyses have revealed the existence of class-dependent and -independent local motifs involved in the overall fold of the ligand-binding domain (LBD) in the nuclear receptor (NR) superfamily. Of these local motifs, three local motifs, i.e., AF-2 fixed motifs, were involved in the agonist conformation of the activation function-2 (AF-2) region of the LBD. Receptor-agonist interactions increased the stability of these AF-2 fixed motifs in the agonist conformation. In contrast, perturbation of the AF-2 fixed motifs by a ligand or another protein molecule led the AF-2 architecture to adopt an antagonist conformation. Knowledge of this process should provide us with novel insights into the agonism and antagonism of NRs.

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