Conformational changes in human prolyl-tRNA synthetase upon binding of the substrates proline and ATP and the inhibitor halofuginone

Jonghyeon Son, Eun Hye Lee, Minyoung Park, Jong Hyun Kim, Junsoo Kim, Sunghoon Kim, Young Ho Jeon, Kwang Yeon Hwang

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Aminoacyl-tRNA synthetases recognize cognate amino acids and tRNAs from their noncognate counterparts and catalyze the formation of aminoacyl-tRNAs. Halofuginone (HF), a coccidiostat used in veterinary medicine, exerts its effects by acting as a high-affinity inhibitor of the enzyme glutamyl-prolyl-tRNA synthetase (EPRS). In order to elucidate the precise molecular basis of this inhibition mechanism of human EPRS, the crystal structures of the prolyl-tRNA synthetase domain of human EPRS (hPRS) at 2.414;Å resolution (hPRS-apo), of hPRS complexed with ATP and the substrate proline at 2.314;Å resolution (hPRS-sub) and of hPRS complexed with HF at 2.6214;Å resolution (hPRS-HF) are presented. These structures show plainly that motif 1 functions as a cap in hPRS, which is loosely opened in hPRS-apo, tightly closed in hPRS-sub and incorrectly closed in hPRS-HF. In addition, the structural analyses are consistent with more effective binding of hPRS to HF with ATP. Mutagenesis and biochemical analysis confirmed the key roles of two residues, Phe1097 and Arg1152, in the HF inhibition mechanism. These structures will lead to the development of more potent and selective hPRS inhibitors for promoting inflammatory resolution.

Original languageEnglish
Pages (from-to)2136-2145
Number of pages10
JournalActa Crystallographica Section D: Biological Crystallography
Volume69
Issue number10
DOIs
Publication statusPublished - 2013 Oct 1

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Proline
Adenosine Triphosphate
prolyl T RNA synthetase
halofuginone
Coccidiostats
Amino Acid-Specific Transfer RNA
Amino Acyl-tRNA Synthetases
Veterinary Medicine
Enzyme Inhibitors
Enzymes
Transfer RNA
Mutagenesis

Keywords

  • drug design
  • glutamyl-prolyl-tRNA synthetase
  • herbal inhibitor
  • inflammation
  • multisynthetase complex

ASJC Scopus subject areas

  • Structural Biology

Cite this

Conformational changes in human prolyl-tRNA synthetase upon binding of the substrates proline and ATP and the inhibitor halofuginone. / Son, Jonghyeon; Lee, Eun Hye; Park, Minyoung; Kim, Jong Hyun; Kim, Junsoo; Kim, Sunghoon; Jeon, Young Ho; Hwang, Kwang Yeon.

In: Acta Crystallographica Section D: Biological Crystallography, Vol. 69, No. 10, 01.10.2013, p. 2136-2145.

Research output: Contribution to journalArticle

Son, Jonghyeon ; Lee, Eun Hye ; Park, Minyoung ; Kim, Jong Hyun ; Kim, Junsoo ; Kim, Sunghoon ; Jeon, Young Ho ; Hwang, Kwang Yeon. / Conformational changes in human prolyl-tRNA synthetase upon binding of the substrates proline and ATP and the inhibitor halofuginone. In: Acta Crystallographica Section D: Biological Crystallography. 2013 ; Vol. 69, No. 10. pp. 2136-2145.
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