CRYSTAL-STRUCTURES OF CELLULAR RETINOIC ACID-BINDING PROTEIN-I AND PROTEIN-II IN COMPLEX WITH ALL-TRANS-RETINOIC ACID AND A SYNTHETIC RETINOID

Background: Retinoic acid (RA) plays a fundamental role in diverse cel lular activities. Cellular RA binding proteins (CRABPs) are thought to act by modulating the amount of RA available to nuclear RA receptors. CRABPs and cellular retinol-binding proteins (CRBPs) share a unique f old of two orthogonal beta-sheets that encapsulate their ligands. It h as been suggested that a trio of residues are the prime determinants d efining the high specificity of CRBPs and CRABPs for their physiologic al ligands. Results: Bovine/murine CRABP I and human CRABP II have bee n crystallized in complex with their natural ligand, all-trans-RA. Hum an CRABP II has also been crystallized in complex with a synthetic ret inoid, 'compound 19'. Their structures have been determined and refine d at resolutions of 2.9 Angstrom, 1.8 Angstrom and 2.2 Angstrom, respe ctively. Conclusions: The retinoid-binding site in CRABPs differs sign ificantly from that observed in CRBP. Structural changes in three juxt aposed areas of the protein create a new, displaced binding site for R A. The carboxylate of the ligand interacts with the expected trio of r esidues (Arg132, Tyr134 and Arg111; CRABP II numbering). The RA ligand is almost nat with the beta-ionone ring showing a significant deviati on (-33 degrees) from a cis conformation relative to the isoprene tail . The edge atoms of the beta-ionone ring are accessible to solvent in a suitable orientation for presentation to metabolizing enzymes. The b ulkier synthetic retinoid causes small conformational changes in the p rotein structure.