7U4C

Borrelia burgdorferi HtpG N-terminal domain (1-228) in complex with BX-2819

7U4C の概要

• エントリーDOI: 10.2210/pdb7u4c/pdb
• 分子名称: Chaperone protein HtpG, ethyl (4-{3-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-5-sulfanyl-4H-1,2,4-triazol-4-yl}benzyl)carbamate (3 entities in total)
• 機能のキーワード: inhibitor, chaperone-inhibitor complex, chaperone/inhibitor
• 由来する生物種: Borreliella burgdorferi (Lyme disease spirochete)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 55062.58

構造登録者

Kowalewski, M.E.,Lietzan, A.,Haystead, T.,Redinbo, M.R. (登録日: 2022-02-28, 公開日: 2023-03-08, 最終更新日: 2023-11-15)

主引用文献

Carlson, D.L.,Kowalewski, M.,Bodoor, K.,Lietzan, A.D.,Hughes, P.F.,Gooden, D.,Loiselle, D.L.,Alcorta, D.,Dingman, Z.,Mueller, E.A.,Irnov, I.,Modla, S.,Chaya, T.,Caplan, J.,Embers, M.,Miller, J.C.,Jacobs-Wagner, C.,Redinbo, M.R.,Spector, N.,Haystead, T.A.J.
Targeting Borrelia burgdorferi HtpG with a berserker molecule, a strategy for anti-microbial development.
Cell Chem Biol, 2023

PubMed Abstract: Conventional antimicrobial discovery relies on targeting essential enzymes in pathogenic organisms, contributing to a paucity of new antibiotics to address resistant strains. Here, by targeting a non-essential enzyme, Borrelia burgdorferi HtpG, to deliver lethal payloads, we expand what can be considered druggable within any pathogen. We synthesized HS-291, an HtpG inhibitor tethered to the photoactive toxin verteporfin. Reactive oxygen species, generated by light, enables HS-291 to sterilize Borrelia cultures by causing oxidation of HtpG, and a discrete subset of proteins in proximity to the chaperone. This caused irreversible nucleoid collapse and membrane blebbing. Tethering verteporfin to the HtpG inhibitor was essential, since free verteporfin was not retained by Borrelia in contrast to HS-291. For this reason, we liken HS-291 to a berserker, wreaking havoc upon the pathogen's biology once selectively absorbed and activated. This strategy expands the druggable pathogenic genome and offsets antibiotic resistance by targeting non-essential proteins.

PubMed: 37918401
DOI: 10.1016/j.chembiol.2023.10.004

実験手法

X-RAY DIFFRACTION (2.28 Å)