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Structural Evaluation of the Agonistic Action of a Vitamin D Analog with Two Side Chains Binding to the Nuclear Vitamin D Receptor

Departments of Biochemistry (S.V., C.C.) and Chemistry (M.P., J.I.K.), University of Kuopio, Kuopio, Finland; and BioXell, Nutley, New Jersey (M.R.U.)

The vitamin D receptor (VDR) is one of the endocrine members of the nuclear receptor superfamily and has a characteristic high affinity for its natural ligand 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]. From a mechanistic point of view, the most interesting analog of 1,25(OH)₂D₃ is the one that carries two side chains, referred to as Gemini. In this study, molecular dynamics (MD) simulations of the Gemini-VDR complex were performed that demonstrated that the binding of a ligand with a 25% increased volume does not disturb the overall structure of the ligand-binding domain (LBD). It was found that one of the two side chains takes exactly the same position as the single side chain of the natural ligand, which suggests that the molecular mechanism of the agonism of Gemini is identical to that of 1,25(OH)₂D₃. VDR single and double point mutants at L227, A303, I313, and L397 and in vitro and ex vivo assessment of their agonistic action confirmed the predictions of the MD simulations. Moreover, it was found that the second side chain of Gemini can choose between two binding positions within the ligand-binding pocket of the VDR. These two newly identified "corners" were characterized most specifically by the amino acids pairs L227/A303 and I313/L397. Therefore, Gemini is an important model compound that allows further insight into the molecular actions of the VDR but is, in parallel, also a promising precursor for the design of even more potent 1,25(OH)₂D₃ analogs.

Address correspondence to: Prof. Carsten Carlberg, Department of Biochemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. E-mail: carlberg{at}messi.uku.fi

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