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Halogen‐π Interactions in the Cytochrome P450 Active Site: Structural Insights into Human P450 2B6 Substrate Selectivity.
Author(s) -
Shah Manish B,
Liu Jingbao,
Zhang Qinghai,
Stout C. David,
Halpert James R
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb614
Subject(s) - bromine , active site , chemistry , bromide , halogen , selectivity , substrate (aquarium) , stereochemistry , cyp2b6 , enzyme , cytochrome p450 , organic chemistry , biology , catalysis , ecology , alkyl , cyp3a4
Numerous CYP2B6 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 Phe‐108 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 Phe‐297 in CYP2B6, whereas the two major orientations in the active site mutant I114V exhibited bromine‐π interactions with two additional residues, Phe‐108 and Phe‐115. 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. Support or Funding Information ES003619 to Dr. James R. Halpert