2. Academic Validation
  3. Girolline is a sequence context-selective modulator of eIF5A activity

Girolline is a sequence context-selective modulator of eIF5A activity

  • Nat Commun. 2025 Jan 10;16(1):223. doi: 10.1038/s41467-024-54838-2.
Tilman Schneider-Poetsch 1,  Yongjun Dang 2,  Wakana Iwasaki 3,  Mayumi Arata 4,  Yuichi Shichino 5,  Ali Al Mourabit 6,  Celine Moriou 6,  Daniel Romo 7,  Jun O Liu 8,  Takuhiro Ito 3,  Shintaro Iwasaki 5 9,  Minoru Yoshida 10 11 12 13
Affiliations

Affiliations

  • 1 Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan. tsp@riken.jp.
  • 2 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, College of Pharmacy, Chongqing Medical University, Chongqing, China.
  • 3 Laboratory for Translation Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan.
  • 4 Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.
  • 5 RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan.
  • 6 Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Univ. Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.
  • 7 Department of Chemistry and Biochemistry, Baylor University, One Bear Place, Waco, USA.
  • 8 Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 9 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
  • 10 Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan. yoshidam@riken.jp.
  • 11 Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan. yoshidam@riken.jp.
  • 12 Office of University Professors, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. yoshidam@riken.jp.
  • 13 Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. yoshidam@riken.jp.
PMID: 39794322 DOI: 10.1038/s41467-024-54838-2
Abstract

Natural products have a long history of providing probes into protein biosynthesis, with many of these compounds serving as therapeutics. The marine natural product girolline has been described as an inhibitor of protein synthesis. Its precise mechanism of action, however, has remained unknown. The data we present here suggests that girolline is a sequence-selective modulator of translation factor eIF5A. Girolline interferes with ribosome-eIF5A interaction and induces ribosome stalling where translational progress is impeded, including on AAA-encoded lysine. Our data furthermore indicate that eIF5A plays a physiological role in ribosome-associated quality control and in maintaining the efficiency of translational progress. Girolline helped to deepen our understanding of the interplay between protein production and quality control in a physiological setting and offers a potent chemical tool to selectively modulate gene expression.

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