한빛사논문
- 조회2,192
Abstract
Jonghyeon Son,a‡ Eun Hye Lee,a‡ Minyoung Park,b,c Jong Hyun Kim,b,c Junsoo Kim,a Sunghoon Kim,b,c Young Ho Jeond and Kwang Yeon Hwanga*
aDepartment of Biosystems and Biotechnology, Korea University, Anam-dong 5, Seongbuk-gu, Seoul 136-701, Republic of Korea,
bMedicinal Bioconvergence Research Center, Advanced Institutes of Convergence Technology, Suwon, Gyeonggi 443-759, Republic of Korea,
cCollegeof Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea, and
dCollege of Pharmacy, Korea University, Sejong-ro 2511, Sejong, Chungnam 136-713, Republic of Korea
‡ These authors made equal contributions.
*Correspondence
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 2.4Å resolution (hPRS-apo), of hPRS complexed with ATP and the substrate proline at 2.3 Å resolution (hPRS-sub) and of hPRS complexed with HF at 2.62 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.
Keywords: glutamyl-prolyl-tRNA synthetase; multisynthetase complex; herbal inhibitor; inflammation; drug design
논문정보
- Research article
- 2013년 10월 (BRIC 등록일 2013-09-27)
- 국내 연구진
- 생명과학 > 생화학
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