2. Academic Validation
  3. Structural basis for differential inhibition of eukaryotic ribosomes by tigecycline

Structural basis for differential inhibition of eukaryotic ribosomes by tigecycline

  • Nat Commun. 2024 Jun 28;15(1):5481. doi: 10.1038/s41467-024-49797-7.
Xiang Li # 1,  Mengjiao Wang # 1,  Timo Denk # 2,  Robert Buschauer 2,  Yi Li 1,  Roland Beckmann 3,  Jingdong Cheng 4
Affiliations

Affiliations

  • 1 Minhang Hospital & Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Fudan University, Shanghai, China.
  • 2 Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
  • 3 Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany. beckmann@genzentrum.lmu.de.
  • 4 Minhang Hospital & Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Fudan University, Shanghai, China. cheng@fudan.edu.cn.
  • # Contributed equally.
PMID: 38942792 DOI: 10.1038/s41467-024-49797-7
Abstract

Tigecycline is widely used for treating complicated Bacterial infections for which there are no effective drugs. It inhibits Bacterial protein translation by blocking the ribosomal A-site. However, even though it is also cytotoxic for human cells, the molecular mechanism of its inhibition remains unclear. Here, we present cryo-EM structures of tigecycline-bound human mitochondrial 55S, 39S, cytoplasmic 80S and yeast cytoplasmic 80S ribosomes. We find that at clinically relevant concentrations, tigecycline effectively targets human 55S mitoribosomes, potentially, by hindering A-site tRNA accommodation and by blocking the peptidyl transfer center. In contrast, tigecycline does not bind to human 80S ribosomes under physiological concentrations. However, at high tigecycline concentrations, in addition to blocking the A-site, both human and yeast 80S ribosomes bind tigecycline at another conserved binding site restricting the movement of the L1 stalk. In conclusion, the observed distinct binding properties of tigecycline may guide new pathways for drug design and therapy.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z