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Modeling of electrostatic recognition processes in the mammalian mitochondrial steroid hydroxylase system

Item Type:Article
Title:Modeling of electrostatic recognition processes in the mammalian mitochondrial steroid hydroxylase system
Creators Name:Mueller, J.J. and Lapko, A. and Ruckpaul, K. and Heinemann, U.
Abstract:Adrenodoxin reductase (AR) and adrenodoxin (Adx) are components of the mammalian mitochondrial steroid-hydroxylating system. Crystal structures of Adx, AR and a cross-linked Adx-AR complex have recently been determined. Based on these, we have carried out a modeling and docking study to characterize the recognition between AR, Adx and cytochrome c (Cytc). To rationalize the recognition process, electrostatic potentials were calculated by solving the Poisson-Boltzmann equations. In the Adx-AR complex modeled, a negatively charged surface of Adx recognizes a positive surface of AR, as in the crystal structure of the Adx-AR complex, proving the correct parameterization for the energy calculations. After forming salt bridges between the polar primary binding sites of Adx and AR, charge compensation causes a domain movement in AR, which closes the binding cleft by 2-4 Å. Thereby, a secondary polar binding site is closed and the electron transfer pathways between the FAD of AR and the [2Fe-2S] cluster of Adx are adjusted. Next, the model structure of a complex between Adx and Cytc was derived. The lowest-energy complex between Adx and Cytc matches earlier chemical modification and cross-linking experiments, which proposed polar interactions of Lys13, Lys27, Lys72 and Lys79 of Cytc with acidic residues in Adx. Because of the short distance of 9.4 Å between the redox centers, a complex, productive in electron transfer via a different outlet pathway from the inlet route in Adx, is expected. However, a ternary complex cannot be formed between the Adx-AR complex and Cytc because of steric hindrance. Therefore, a shuttle model for the role of Adx in the electron transfer process to Cytc is preferable to a relay model. In addition, no preferable docking site could be detected for a second Adx when probing the Adx-AR complex, which is required for a quaternary organized-cluster model of all redox partners of the hydroxylase system.
Keywords:Adrenodoxin, Adrenodoxin Reductase, Cytochrome C, Electrostatic Recognition, Modeling of Complex Building, Animals, Cattle
Source:Biophysical Chemistry
Page Range:281-292
Date:December 2002
Official Publication:https://doi.org/10.1016/S0301-4622(02)00286-7
PubMed:View item in PubMed

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