Open AccessX-ray crystallographic identification of a protein-binding site for both all-trans- and 9-cis-retinoic acid.
Author(s) -
Marcia E. Newcomer,
R S Pappas,
David E. Ong
Publication year - 1993
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.90.19.9223
Subject(s) - retinoic acid , retinoic acid receptor , retinoic acid receptor gamma , retinoid x receptor gamma , retinoic acid inducible orphan g protein coupled receptor , retinoid x receptor , retinoic acid receptor alpha , retinoic acid receptor beta , nuclear receptor , chemistry , retinoid , receptor , biochemistry , biology , stereochemistry , transcription factor , gene
The elucidation of how a protein-binding site might specifically recognize both the all-trans and 9-cis isomers of retinoic acid is of particular interest because of the recently discovered binding specificities of the nuclear receptors for retinoic acid. Two families of nuclear receptors for retinoic acid have been described, which are designated RAR (for retinoic acid receptor) and RXR (for retinoid-X receptor). The RXR family of receptors is specific for 9-cis-retinoic acid, whereas the RAR-type receptor is activated by either 9-cis- or all-trans-retinoic acid. During the x-ray structure determination of a secreted epididymal retinoic acid-binding protein, with and without retinoic acid, we observed an electron density for the bound all-trans-retinoic acid that indicates the protein-bound all-trans form of the vitamin/hormone adopts a horseshoe-like conformation that resembles the structure of the 9-cis isomer of the ligand. We detail here the experiments that indicate the electron density is indeed due to all-trans-retinoic acid and that protein can also bind the 9-cis isomer. This observation and the fact that the same protein also binds the synthetic retinoid (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1- propenyl]-benzoic acid (TTNPB), a retinoic acid analog that activates RAR but does not activate RXR, suggest that the mechanism by which this protein recognizes both 9-cis- and all-trans-retinoic acids may be analogous to the mechanism used by RAR. Three crystallographic structures of retinol-binding proteins have been described. In each of these structures the retinol binds with the isoprene tail fully extended. This report represents an x-ray crystallographic description of a protein-bound retinoid conformer that adopts a nonextended conformation, and we believe this observation is relevant to the ligand specificities described for the retinoic acid receptors.