Tracking protein-protein interactions by NMR: conformational selection in human steroidogenic cytochrome P450 CYP17A1 induced by cytochrome b5

Phys Chem Chem Phys. 2024 Jun 19;26(24):16980-16988. doi: 10.1039/d4cp01268b.

Abstract

The human steroidogenic cytochrome P450 CYP17A1 catalyzes two types of reactions in the biosynthetic pathway leading from pregnenolone to testosterone and several other steroid hormones. The first is the hydroxylation of pregnenolone or progesterone to the corresponding 17α-hydroxy steroid, followed by a lyase reaction that converts these 17α-hydroxy intermediates to the androgens dehydroepiandrosterone and androstenedione, respectively. cytochrome b5 (cytb5) is known to act as both an effector and electron donor for the lyase oxidations, markedly stimulating the rate of the lyase reaction in its presence relative to the rate in its absence. Extensive sequential backbone 1H,15N and 13C nuclear magnetic resonance assignments have now been made for oxidized CYP17A1 bound to the prostate cancer drug and inhibitor abiraterone. This is the first eukaryotic P450 for which such assignments are now available. These assignments allow more complete interpretation of the structural perturbations observed upon cytb5 addition. Possible mechanism(s) for the effector activity of cytb5 are discussed in light of this new information.

MeSH terms

  • Androstenes / chemistry
  • Androstenes / metabolism
  • Cytochromes b5* / chemistry
  • Cytochromes b5* / metabolism
  • Humans
  • Magnetic Resonance Spectroscopy
  • Nuclear Magnetic Resonance, Biomolecular
  • Oxidation-Reduction
  • Protein Binding
  • Protein Conformation
  • Steroid 17-alpha-Hydroxylase* / chemistry
  • Steroid 17-alpha-Hydroxylase* / metabolism

Substances

  • Steroid 17-alpha-Hydroxylase
  • Cytochromes b5
  • CYP17A1 protein, human
  • abiraterone
  • Androstenes