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Halogen-π Interactions in the Cytochrome P450 Active Site: Structural Insights into Human CYP2B6 Substrate
Manish B Shah1, Jingbao Liu1, Qinghai Zhang2
1School of Pharmacy, University of Connecticut , Storrs, Connecticut, United States.
ACS Chemical Biology
|April 4, 2017
Summary
Halogen-π bonds influence how drugs and chemicals bind to cytochrome P450 2B6 enzymes. X-ray crystallography revealed these interactions, showing specific orientations within the enzyme
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Many drugs and environmental chemicals metabolized by cytochrome P450 (CYP) 2B6 contain halogens.
- Understanding substrate interactions within the CYP2B6 active site is crucial for predicting drug metabolism and potential toxicities.
Purpose of the Study:
- To investigate the role of halogen-π bonds in the substrate selectivity and orientation of CYP2B6.
- To elucidate the structural basis of these interactions using X-ray crystallography.
Main Methods:
- X-ray crystallography was employed to determine the structures of four CYP2B6 monoterpenoid complexes.
- Analysis of substrate binding orientations and interactions within the enzyme active site.
Main Results:
- Bornyl bromide showed dual orientations, with a predominant one forming a bromine-π bond with Phe108.
- Bornane exhibited two orientations, with the carbon atom corresponding to the bromine site in bornyl bromide displaced.
- Myrtenyl bromide formed a bromine-π bond with Phe297, and a mutant I114V showed interactions with Phe108 and Phe115.
Conclusions:
- Halogen-π interactions play a significant role in the orientation and binding of halogenated substrates within the CYP2B6 active site.
- These interactions appear to be a distinguishing feature of CYP2B enzymes and are also relevant for CYP3A enzymes.
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