Mechanisms of molecular recognition: crystal structure analysis of human and rat transthyretin inhibitor complexes.
Structure-activity data show that many pharmacological agents are strong competitive inhibitors for thyroxine (T4) binding to transthyretin (TTR) and that this competition can interfere with their normal pharmacological actions. TTR is a tetrameric serum protein responsible for the transport of 20% of the circulating T4 in man, while in lower vertebrates such as rats it is the only carrier. The sequence of rat TTR is 85% homologous to the human protein. Crystallographic analyses of ligand co-crystal complexes of human and rat TTR have been studied to understand the molecular basis for binding selectivity of competitor binding to TTR. Analysis of TTR crystal complexes with several classes of competitors (hormone metabolites, flavonoids, fluorescent probes, analgesics and cardiac agents) revealed multiple modes of binding with both forward and reverse ligand binding orientations. These ligands also have different binding positions along the length of the channel with the smallest ligands located deeper within the hormone domain. Data for the human TTR complex with the bromoflavone EMD21388 incubated at different times revealed variable binding positions and occupancies dependent upon incubation time. Comparison of the structures of T4 thyroacetic acid in complex with both human and rat TTR revealed forward and reverse binding, but also showed different modes of binding in the rat compared to the human complex. These data highlight the importance of hydrogen bonding with Lys-15 and Ser-117 and provide insight into ligand binding affinity and negative cooperativity.
Cody
Vivian
V
Hauptman-Woodward Medical Research Institute, Buffalo, NY 14203, USA. cody@hwi.buffalo.edu
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002316:Cardiotonic Agents / Q000737:chemistry; D018360:Crystallography, X-Ray; D005419:Flavonoids / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011228:Prealbumin / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013963:Thyroid Hormones / Q000737:chemistry* / Q000378:metabolism
D002316:Cardiotonic Agents; D005419:Flavonoids; D008024:Ligands; D011228:Prealbumin; D013963:Thyroid Hormones