tailieunhanh - Báo cáo Y học: A model for recognition of polychlorinated dibenzo-p-dioxins by the aryl hydrocarbon receptor

Ligand binding by the aryl hydrocarbon receptor (AhR), a member of the bHLH-PAS family of transcriptional reg-ulatory proteins, has been mapped to a region within the second ÔPASÕ domain, a conserved sequence motif ®rst discovered in the Per-ARNT-Sim family of proteins. In addition to the bacterial photoactive yellow protein (PYP), which had been proposed as a structural prototype for the three dimensional fold of PAS domains, two crystal structures of the PAS domain have recently been deter-mined: the human potassium channel HERG and the heme binding domain of the bacterial O2 sensing FixL protein. . | Eur. J. Biochem. 269 13-18 2002 FEBS 2002 A model for recognition of polychlorinated dibenzo-p-dioxins by the aryl hydrocarbon receptor M. Procopio1 A. Lahm2 A. Tramontane3 L. Bonati1 and D. Pitea1 1 Dipartimento di Scienze dell Ambiente e del Territorio Universita degli Studi di Milano-Bicocca Milano Italy 2Istituto di Ricerche di Biologia Molecolare P. Angeletti Pomezia Roma Italy 3Dipartimento di Scienze Biochimiche Rossi Fanelli Universita di Roma La Sapienza Roma Italy Ligand binding by the aryl hydrocarbon receptor AhR a member of the bHLH-PAS family of transcriptional regulatory proteins has been mapped to a region within the second PAS domain a conserved sequence motif first discovered in the Per-ARNT-Sim family of proteins. In addition to the bacterial photoactive yellow protein PYP which had been proposed as a structural prototype for the three dimensional fold of PAS domains two crystal structures of the PAS domain have recently been determined the human potassium channel HERG and the heme binding domain of the bacterial O2 sensing FixL protein. The three structures reveal a highly conserved structural framework in evolutionary rather distant PAS domains provide a more general view of how these domains can recognize their ligands and suggest a structure-function relationship that we exploited to build a three-dimensional model of the ligand binding domain LBD of the mouse aryl hydrocarbon receptor mAhR . The model allowed us to putatively identify the residues responsible for the recognition of polychlorinated dibenzo-p-dioxins PCDDs by AhR receptors and to formulate an hypothesis on the signal transduction mechanism. Keywords aryl hydrocarbon receptor polychlorinated dibenzo-p-dioxins structure prediction protein modelling molecular recognition. Studies on the biological mechanism of action of polychlorinated dibenzo-p-dioxins PCDDs indicate that their biological effects are mediated by binding to a specific cytoplasmic protein the aryl hydrocarbon .