Ab initio fragment molecular orbital study of molecular interactions in liganded retinoid X receptor: Specification of residues associated with ligand inducible information transmission

Mika Ito, Kaori Fukuzawa, Takeshi Ishikawa, Yuji Mochizuki, Tatsuya Nakano, Shigenori Tanaka

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

Abstract

The ab initio fragment molecular orbital calculations were performed for the α-subtype of the human retinoid X receptor (hRXRα) complex with its natural ligand 9-cis retinoic acid (9cRA) to quantitatively specify the key residues with important roles for the ligand inducible information transmission of RXR. In the RXR-9cRA complex, the transactivation helix 12 (H12) adopts a canonical agonist conformation, which just corresponds to the transcriptional activation function 2 activating domain core (AF2C). Through the analyses of molecular interactions by the second-order Møller-Plesset perturbation (MP2) method, it was proved that Trp305 and Leu436 of the AF2C binding pocket would be important for the stabilization of the H12 canonical agonist conformation, and, at the same time, for the recognition of the 9cRA molecule. Besides, through the analyses of orbital interactions by the local MP2 (LMP2) method, it was found that Trp305 and Leu436 would recognize the 9cRA molecule especially at its C19 methyl group, which has been most notably targeted to modify for agonist and antagonist design. Moreover, on the basis of the relationships of molecular interactions, it was suggested that the interactions of Trp305 and Leu436 with AF2C residues would be significantiy influenced by the interactions of Trp305 and Leu436 with 9cRA. Taken together, our findings quantitatively demonstrated that Trp305 and Leu436 would be the possible key residues for the information transmission in liganded RXR, accounting for their importance suggested by experiments. Altogether, these results substantiated that our approach is useful for the understanding of the detailed molecular mechanism underlying the transcriptional regulation of RXR and related nuclear receptors at the quantum mechanical level.

Original languageEnglish
Pages (from-to)12081-12094
Number of pages14
JournalJournal of Physical Chemistry B
Volume112
Issue number38
DOIs
Publication statusPublished - 2008 Sep 25
Externally publishedYes

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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