A ligand-entry surface of the nuclear receptor superfamily consists of the helix H3 of the ligand-binding domain

Tsuji, M.

Journal of Molecular Graphics and Modelling 62: 262-275

2015


ISSN/ISBN: 1873-4243
PMID: 26544573
DOI: 10.1016/j.jmgm.2015.10.002
Accession: 057067529

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Abstract
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.