7U4C

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

Summary for 7U4C

• Entry DOI: 10.2210/pdb7u4c/pdb
• Descriptor: 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)
• Functional Keywords: inhibitor, chaperone-inhibitor complex, chaperone/inhibitor
• Biological source: Borreliella burgdorferi (Lyme disease spirochete)
• Total number of polymer chains: 2
• Total formula weight: 55062.58

Authors

Kowalewski, M.E.,Lietzan, A.,Haystead, T.,Redinbo, M.R. (deposition date: 2022-02-28, release date: 2023-03-08, Last modification date: 2023-11-15)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.28 Å)