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Charge Clamps of Lysines and Hydrogen Bonds Play Key Roles in the Mechanism to Fix Helix 12 in the Agonist and Antagonist Positions of Estrogen Receptor α: Intramolecular Interactions Studied by the Ab Initio Fragment Molecular Orbital Method
journal contribution
posted on 2014-05-15, 00:00 authored by Chiduru Watanabe, Kaori Fukuzawa, Shigenori Tanaka, Sachiko Aida-HyugajiThe mechanism to fix helix 12 (H12)
in the agonist/antagonist position,
which is involved in controlling transcriptional activation, of the
human estrogen receptor α ligand binding domain (hERαLBD)
is studied by using fragment molecular orbital calculations at the
Møller–Plesset second-order perturbation levels to analyze
inter-fragment interaction energies (IFIEs), electrostatic potentials
(ESPs), and atomic charges. The mutually attractive and complementary
relationships between H12 and highly conserved Lys529/Lys362 are shown
through the IFIEs and ESPs. The highly conserved Lys529 and Lys362
are found to have strong attractive interactions with the anionic
residues of H12 in the agonist and antagonist positions, respectively,
thus playing roles of charge clamps to fix H12. Additionally, intramolecular
interactions between the neutral residues of H12 including the LXXML
motif and the other part of hERα are strengthened by the hydrogen
bonds and polarization. It is noted that the highly conserved Asp351
forms a hydrogen bond with Leu540 of H12 in the hERα–agonist
complex, while it is also involved in stabilization of ligand binding
in the hERα–antagonist complex. The charges of residues
at the interface between H12 and the other part of hERα approach
approximately neutral upon forming the agonist/antagonist binding
conformation so as to relax the electrostatic repulsion caused by
the negative charges of H12 and the other part of hERα. Our
observations would thus provide useful information to control the
H12 position for regulation of transcription in hERα and other
nuclear receptors.