Structure and function of cytochromes P450:a comparative analysis of three crystal structures

Charles A. Hasemann, Ravi G. Kurumbail, Sekhar S. Boddupalli, Julian A. Peterson, Johann Deisenhofer

Research output: Contribution to journalArticle

591 Scopus citations

Abstract

Background: Cytochromes P450 catalyze the oxidation of a variety of hydrophobic substrates. Sequence identities between P450 families are generally low (10-30%), and consequently, the structure-function correlations among P450s are not clear. The crystal structures of P450terp and the hemoprotein domain of P450BM-3 were recently determined, and are compared here with the previously available structure of P450cam. Results The topology of all three enzymes is quite similar. The heme-binding core structure is well conserved, except for local differences in the I helices. The greatest variation is observed in the substrate-binding regions. The structural superposition of the proteins permits an improved sequence alignment of other P450s. The charge distribution in the three structures is similarly asymmetric and defines a molecular dipole. Conclusion Based on this comparison we believe that all P450s will be found to possess the same tertiary structure. The ability to precisely predict other P450 substrate-contact residues is limited by the extreme structural heterogeneity in the substrate-recognition regions. The central I-helix structures of P450terp and P450BM-3 suggest a role for helix-associated solvent molecules as a source of catalytic protons, distinct from the mechanism for P450cam . We suggest that the P450 molecular dipole might aid in both redox-partner docking and proton recruitment for catalysis.

Original languageEnglish (US)
Pages (from-to)41-62
Number of pages22
JournalStructure
Volume3
Issue number1
DOIs
StatePublished - Jan 1995

Keywords

  • crystal structure
  • cytochrome P450
  • electrostatics
  • hemoprotein
  • monooxygenase

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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