Abstract
Human microsomal cytochrome P450 2E1 (CYP2E1) can oxidize not only low molecular weight xenobiotic compounds such as ethanol, but also many endogenous fatty acids. The crystal structure of CYP2E1 in complex with indazole reveals that the active site is deeply buried into the protein center. Thus, the unbinding pathways and associated unbinding mechanisms remain elusive. In this study, random acceleration molecular dynamics simulations combined with steered molecular dynamics and potential of mean force calculations were performed to identify the possible unbinding pathways in CYP2E1. The results show that channel 2c and 2a are most likely the unbinding channels of CYP2E1. The former channel is located between helices G and I and the B-C loop, and the latter resides between the region formed by the F-G loop, the B-C loop and the β1 sheet. Phe298 and Phe478 act as the gate keeper during indazole unbinding along channel 2c and 2a, respectively. Previous site-directed mutagenesis experiments also supported these findings.
Highlights
The cytochromes P450 (CYPs) are a superfamily of hemecontaining monooxygenases that catalyze metabolism and activation of a variety of endogenous and exogenous compounds
Exploration of channels in cytochrome P450 2E1 (CYP2E1) crystal structures Five crystal structures of CYP2E1 including small weight inhibitors and fatty acids bound complexes are available in Protein Datebase Bank (PDB)
Though the fold structure is similar to other P450s, the active site of CYP2E1 is the smallest in the available human CYP crystal structures
Summary
The cytochromes P450 (CYPs) are a superfamily of hemecontaining monooxygenases that catalyze metabolism and activation of a variety of endogenous and exogenous compounds. Catalyzing biosynthesis and degradation of chemicals is the most common function of P450s in microorganisms, plants and animals. CYPs are absolutely indispensable from the biological and pharmaceutical viewpoints [1]. Crystal structures of more than thirty CYPs from different species have been determined. Despite the low sequence identity (,20%) between some CYPs, their structures display a highly similar structural fold. The active site of CYPs contains a heme group and the iron atom is tethered to CYP via a highly conserved cysteine. Most CYPs adopt a closed conformation, in which the active site is deeply buried in the protein core and inaccessible to the protein exterior. The question of how ligand enters/exits the active site to undergo oxidation or inhibition has drawn much attention
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