Abstract
The bacterial Cytochrome P450 (CYP) BM3 (CYP102A1) is one of the most active CYP isoforms. BM3 mutants can serve as a model for human drug-metabolizing CYPs and/or as biocatalyst for selective formation of drug metabolites. Hence, molecular and computational biologists have in the last two decades shown strong interest in the discovery and design of novel BM3 variants with optimized activity and selectivity for substrate conversion. This led e.g. to the discovery of mutant M11 that is able to metabolize a variety of drugs and drug-like compounds with relatively high activity. In order to further improve our understanding of CYP binding and reactions, we performed a co-crystallization study of mutant M11 and report here the three-dimensional structure M11 in complex with dithiothreitol (DTT) at a resolution of 2.16 Å. The structure shows that DTT can coordinate to the Fe atom in the heme group. UV/Vis spectroscopy and molecular dynamics simulation studies underline this finding and as first structure of the CYP BM3 mutant M11 in complex with a ligand, it offers a basis for structure-based design of novel mutants.
Highlights
The Cytochrome P450 (CYP) enzyme family comprises 57 human isoforms serving various purposes
We presented a crystal structure of CYP BM3 mutant M11 in complex with a ligand
Our crystal structure indicates that binding of a DTT ligand to M11 does not significantly alter the protein conformation, which underlines the use of the structure of this promiscuous enzyme for modeling purposes
Summary
The CYP enzyme family comprises 57 human isoforms serving various purposes. The human CYPs comprise highly selective enzymes involved in e.g. steroidogenesis [2]. These CYPs have been shown to be potential targets for treatment of various forms of cancer [3, 4]. The bacterial CYPs are interesting as targets for certain diseases (e.g. Mycobacterium tuberculosis) [6]. They can be tailored to mimic human CYPs and often be expressed in higher yield than their human analogues [7]
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