CRYSTAL-STRUCTURES OF CELLULAR RETINOIC ACID-BINDING PROTEIN-I AND PROTEIN-II IN COMPLEX WITH ALL-TRANS-RETINOIC ACID AND A SYNTHETIC RETINOID
1994 (English)In: STRUCTURE, ISSN 0969-2126, Vol. 2, no 12, 1241-1258 p.Article in journal (Refereed) Published
BACKGROUND: Retinoic acid (RA) plays a fundamental role in diverse cellular 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 fold of two orthogonal beta-sheets that encapsulate their ligands. It has been suggested that a trio of residues are the prime determinants defining the high specificity of CRBPs and CRABPs for their physiological ligands. RESULTS: Bovine/murine CRABP I and human CRABP II have been crystallized in complex with their natural ligand, all-trans-RA. Human CRABP II has also been crystallized in complex with a synthetic retinoid, 'compound 19'. Their structures have been determined and refined at resolutions of 2.9 A, 1.8 A and 2.2 A, respectively. CONCLUSIONS: The retinoid-binding site in CRABPs differs significantly from that observed in CRBP. Structural changes in three juxtaposed areas of the protein create a new, displaced binding site for RA. The carboxylate of the ligand interacts with the expected trio of residues (Arg132, Tyr134 and Arg111; CRABP II numbering). The RA ligand is almost flat with the beta-ionone ring showing a significant deviation (-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 bulkier synthetic retinoid causes small conformational changes in the protein structure.
Place, publisher, year, edition, pages
1994. Vol. 2, no 12, 1241-1258 p.
ALL-TRANS-RETINOIC ACID; CHIRAL SEPARATOR; MOLECULAR RECOGNITION; RETINOIC ACID BINDING PROTEINS; NUCLEAR-MAGNETIC-RESONANCE; SITE-DIRECTED MUTAGENESIS; P2 MYELIN PROTEIN; ESCHERICHIA-COLI; CRABP-I; 3-DIMENSIONAL STRUCTURE; CRYSTALLOGRAPHIC REFINEMENT; MO
IdentifiersURN: urn:nbn:se:uu:diva-80598OAI: oai:DiVA.org:uu-80598DiVA: diva2:108512