Multiple drug binding modes in Mycobacterium tuberculosis CYP51B1

J Inorg Biochem. 2020 Apr:205:110994. doi: 10.1016/j.jinorgbio.2020.110994. Epub 2020 Jan 13.

Abstract

The Mycobacterium tuberculosis (Mtb) genome encodes 20 different cytochrome P450 enzymes (CYPs), many of which serve essential biosynthetic roles. CYP51B1, the Mtb version of eukaryotic sterol demethylase, remains a potential therapeutic target. The binding of three drug fragments containing nitrogen heterocycles to CYP51B1 is studied here by continuous wave (CW) and pulsed electron paramagnetic resonance (EPR) techniques to determine how each drug fragment binds to the heme active-site. All three drug fragments form a mixture of complexes, some of which retain the axial water ligand from the resting state. Hyperfine sublevel correlation spectroscopy (HYSCORE) and electron-nuclear double resonance spectroscopy (ENDOR) observe protons of the axial water and on the drug fragments that reveal drug binding modes. Binding in CYP51B1 is complicated by the presence of multiple binding modes that coexist in the same solution. These results aid our understanding of CYP-inhibitor interactions and will help guide future inhibitor design.

Keywords: Cytochrome P450; EPR; HYSCORE; Mycobacterium tuberculosis.

Publication types

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

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Bacterial Proteins* / antagonists & inhibitors
  • Bacterial Proteins* / chemistry
  • Catalytic Domain
  • Cytochrome P-450 Enzyme Inhibitors / chemistry*
  • Cytochrome P-450 Enzyme System* / chemistry
  • Mycobacterium tuberculosis / enzymology*

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System
  • cytochrome P-450 CYP51, Mycobacterium tuberculosis