Solution Conformations and Dynamics of Substrate-Bound Cytochrome P450 MycG.
Solution Conformations and Dynamics of Substrate-Bound Cytochrome P450 MycG.
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DOI：
10.1021/acs.biochem.7b00291
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发表时间：
2017-05-30
期刊：
影响因子：
2.9
通讯作者：
Pochapsky TC
中科院分区：
文献类型：
--
作者：
Tietz DR;Podust LM;Sherman DH;Pochapsky TC
MycG is a P450 monoxygenase that catalyzes the sequential hydroxylation and epoxidation of mycinamicin IV (M-IV), the last two steps in the biosynthesis of mycinamicin II, a macrolide antibiotic isolated from M. griseorubida. The crystal structure of MycG with M-IV bound was previously determined, but showed the bound substrate in an orientation that did not rationalize the observed regiochemistry of M-IV hydroxylation. NMR paramagnetic relaxation enhancements (PRE) gave evidence for an orientation of M-IV in the MycG active site more compatible with the observed chemistry, but substrate-induced changes in the enzyme structure were not characterized. We now describe the use of amide 1H-15N residual dipolar couplings (RDCs) as experimental restraints in solvated “soft annealing” molecular dynamics simulations to generate solution structural ensembles of M-IV-bound MycG. Chemical shift perturbations, hydrogen-deuterium exchange and 15N relaxation behavior provide insight into dynamic and electronic perturbations in the MycG structure in response to M-IV binding. The solution and crystallographic structures are compared, and the possibility that the crystallographic orientation of bound M-IV represents an inhibitory mode is discussed.
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