Specific glycine-dependent enzyme motion determines the potency of conformation selective inhibitors of threonyl-tRNA synthetase.

Threonine-tRNA Ligase / metabolism Glycine / chemistry Protein Conformation Enzyme Inhibitors / chemistry Anti-Bacterial Agents / pharmacology Mutation Pseudomonas fluorescens / enzymology

Journal

Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179

Informations de publication

Date de publication:
16 Jul 2024
Historique:
received: 26 02 2024
accepted: 05 07 2024
medline: 17 7 2024
pubmed: 17 7 2024
entrez: 16 7 2024
Statut: epublish

Résumé

The function of proteins depends on their correct structure and proper dynamics. Understanding the dynamics of target proteins facilitates drug design and development. However, dynamic information is often hidden in the spatial structure of proteins. It is important but difficult to identify the specific residues that play a decisive role in protein dynamics. Here, we report that a critical glycine residue (Gly463) dominates the motion of threonyl-tRNA synthetase (ThrRS) and the sensitivity of the enzyme to antibiotics. Obafluorin (OB), a natural antibiotic, is a novel covalent inhibitor of ThrRS. The binding of OB induces a large conformational change in ThrRS. Through five crystal structures, biochemical and biophysical analyses, and computational simulations, we found that Gly463 plays an important role in the dynamics of ThrRS. Mutating this flexible residue into more rigid residues did not damage the enzyme's three-dimensional structure but significantly improved the thermal stability of the enzyme and suppressed its ability to change conformation. These mutations cause resistance of ThrRS to antibiotics that are conformationally selective, such as OB and borrelidin. This work not only elucidates the molecular mechanism of the self-resistance of OB-producing Pseudomonas fluorescens but also emphasizes the importance of backbone kinetics for aminoacyl-tRNA synthetase-targeting drug development.

Identifiants

DOI: 10.1038/s42003-024-06559-x PMID: 39014102
pubmed: 39014102
doi: 10.1038/s42003-024-06559-x
pii: 10.1038/s42003-024-06559-x
doi:

Substances chimiques

Threonine-tRNA Ligase EC 6.1.1.3
Glycine TE7660XO1C
Enzyme Inhibitors 0
Anti-Bacterial Agents 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

867

Subventions

Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 22277132, 22277134
Organisme : Shanghai Science and Technology Development Foundation (Shanghai Science and Technology Development Fund)
ID : 22ZR1475000

Informations de copyright

© 2024. The Author(s).

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Auteurs

Hang Qiao (H)

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, 200032, Shanghai, China.

Zilu Wang (Z)

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, 200032, Shanghai, China.

Hao Yang (H)

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, 201210, Shanghai, China.
ORCID: 0009-0008-0040-276X

Mingyu Xia (M)

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, 200032, Shanghai, China.

Guang Yang (G)

School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, 310024, Hangzhou, China.

Fang Bai (F)

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, 201210, Shanghai, China. baifang@shanghaitech.edu.cn.
School of Information Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, 201210, Shanghai, China. baifang@shanghaitech.edu.cn.
Shanghai Clinical Research and Trial Center, 201210, Shanghai, China. baifang@shanghaitech.edu.cn.
ORCID: 0000-0003-1468-5568

Jing Wang (J)

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, 200032, Shanghai, China. JWang@sioc.ac.cn.
School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, 310024, Hangzhou, China. JWang@sioc.ac.cn.
ORCID: 0000-0002-7566-1212

Pengfei Fang (P)

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, 200032, Shanghai, China. FangPengfei@sioc.ac.cn.
School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, 310024, Hangzhou, China. FangPengfei@sioc.ac.cn.
Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, 510006, Guangzhou, China. FangPengfei@sioc.ac.cn.
ORCID: 0000-0002-3448-5494

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Classifications MeSH

questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Ligases › Carbon-oxygen ligases › Amino acyl-tRNA synthetases › Threonine-tRNA ligase › Specific glycine-dependent enzyme motion...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Glycine › Specific glycine-dependent enzyme motion...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Specific glycine-dependent enzyme motion...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Specific glycine-dependent enzyme motion...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antibactériens › Specific glycine-dependent enzyme motion...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Specific glycine-dependent enzyme motion...
questionsmedicales.fr › Bactéries › Proteobacteria › Gammaproteobacteria › Pseudomonadaceae › Pseudomonas › Pseudomonas fluorescens › Specific glycine-dependent enzyme motion...