Structural features of cytochromes P450 and ligands that affect drug metabolism as revealed by X-ray crystallography and NMR

Future Med Chem. 2010 Sep;2(9):1451-68. doi: 10.4155/fmc.10.229.


Cytochromes P450 (P450s) play a major role in the clearance of drugs, toxins, and environmental pollutants. Additionally, metabolism by P450s can result in toxic or carcinogenic products. The metabolism of pharmaceuticals by P450s is a major concern during the design of new drug candidates. Determining the interactions between P450s and compounds of very diverse structures is complicated by the variability in P450-ligand interactions. Understanding the protein structural elements and the chemical attributes of ligands that dictate their orientation in the P450 active site will aid in the development of effective and safe therapeutic agents. The goal of this review is to describe P450-ligand interactions from two perspectives. The first is the various structural elements that microsomal P450s have at their disposal to assume the different conformations observed in X-ray crystal structures. The second is P450-ligand dynamics analyzed by NMR relaxation studies.

Keywords: Cytochrome P450; NMR; P450; X-ray crystallography; drug metabolism; mammalian; microsomal; plasticity; protein structure; xenobiotic.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Crystallography, X-Ray / methods*
  • Cytochrome P-450 Enzyme System / chemistry*
  • Cytochrome P-450 Enzyme System / metabolism
  • Ligands
  • Magnetic Resonance Spectroscopy / methods*
  • Models, Molecular
  • Pharmacokinetics*
  • Protein Conformation
  • Substrate Specificity


  • Ligands
  • Cytochrome P-450 Enzyme System