Halogen-π Interactions in the Cytochrome P450 Active Site: Structural Insights into Human CYP2B6 Substrate Selectivity

ACS Chem Biol. 2017 May 19;12(5):1204-1210. doi: 10.1021/acschembio.7b00056. Epub 2017 Apr 6.


Numerous cytochrome P450 (CYP) 2B6 substrates including drugs and environmental chemicals are halogenated. To assess the role of halogen-π bonds in substrate selectivity and orientation in the active site, structures of four CYP2B6 monoterpenoid complexes were solved by X-ray crystallography. Bornyl bromide exhibited dual orientations in the active site with the predominant orientation revealing a bromine-π bond with the Phe108 side chain. Bornane demonstrated two orientations with equal occupancy; in both, the C2 atom that bears the bromine in bornyl bromide was displaced by more than 2.5 Å compared with the latter complex. The bromine in myrtenyl bromide π-bonded with Phe297 in CYP2B6, whereas the two major orientations in the active site mutant I114V exhibited bromine-π interactions with two additional residues, Phe108 and Phe115. Analysis of existing structures suggests that halogen-π interactions may be unique to the CYP2B enzymes within CYP family 2 but are also important for CYP3A enzymes.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Catalytic Domain*
  • Crystallography, X-Ray
  • Cytochrome P-450 CYP2B6 / chemistry*
  • Halogens / chemistry*
  • Humans
  • Monoterpenes / chemistry
  • Protein Binding
  • Substrate Specificity


  • Halogens
  • Monoterpenes
  • Cytochrome P-450 CYP2B6