No Cover Image

Journal article 98 views 20 downloads

Crystal structure of cytochrome P450 NysL and the structural basis for stereo- and regio- selective oxidation of antifungal macrolides

Vidhi C Murarka, Jenny S Kim, David Lamb Orcid Logo, Steven L Kelly, Thomas L Poulos, Alec H Follmer

The Journal of Biological Chemistry, Volume: 301, Issue: 3, Start page: 108185

Swansea University Author: David Lamb Orcid Logo

  • 68750.VOR.pdf

    PDF | Version of Record

    © 2025 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY-NC-ND license.

    Download (2.72MB)

Check full text

DOI (Published version): 10.1016/j.jbc.2025.108185

Abstract

NysL, a cytochrome P450 monooxygenase from the Gram-positive bacterium Streptomyces noursei, catalyzes the C10 hydroxylation of 10-deoxynystain to nystatin A1, a clinically important antifungal. In this study, we present the 2.0 Å resolution crystal structure of NysL bound to nystatin A1. The struct...

Full description

Published in: The Journal of Biological Chemistry
ISSN: 0021-9258 1083-351X
Published: Elsevier Inc 2025
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa68750
Abstract: NysL, a cytochrome P450 monooxygenase from the Gram-positive bacterium Streptomyces noursei, catalyzes the C10 hydroxylation of 10-deoxynystain to nystatin A1, a clinically important antifungal. In this study, we present the 2.0 Å resolution crystal structure of NysL bound to nystatin A1. The structure of this complex provides key insights into the structural elements that dictate the regio- and stereo-selective oxidation of large 20-44-membered macrolide substrates. The closely related AmphL operates on a similar 38-member macrolide but oxidizes C8 rather than C10. This difference requires that the substrate for AmphL penetrate further into the active site relative to NysL. The depth of substrate penetration is controlled by interactions between an area of the substrate binding pocket deemed the “back-wall” and the hemiketal ring of the macrolide substrate.
Keywords: cytochrome P450; substrate specificity; antifungal; crystal structure
College: Faculty of Medicine, Health and Life Sciences
Funders: This work was supported by NIH grant GM131920 (T.L.P.). A.H.F. acknowledges partial support from GM120349 (Andrew S. Borovik). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.
Issue: 3
Start Page: 108185

Similar Items