4K88
Crystal structure of human prolyl-tRNA synthetase (halofuginone bound form)
Summary for 4K88
| Entry DOI | 10.2210/pdb4k88/pdb |
| Related | 4K86 4K87 |
| Descriptor | Proline--tRNA ligase, ZINC ION, 7-bromo-6-chloro-3-{3-[(2R,3S)-3-hydroxypiperidin-2-yl]-2-oxopropyl}quinazolin-4(3H)-one, ... (4 entities in total) |
| Functional Keywords | class ii trna synthetase, ligase, zinc binding, cytosol, ligase-ligase inhibitor complex, ligase/ligase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 61028.19 |
| Authors | Hwang, K.Y.,Son, J.H.,Lee, E.H. (deposition date: 2013-04-18, release date: 2013-10-09, Last modification date: 2024-03-20) |
| Primary citation | Son, J.,Lee, E.H.,Park, M.,Kim, J.H.,Kim, J.,Kim, S.,Jeon, Y.H.,Hwang, K.Y. Conformational changes in human prolyl-tRNA synthetase upon binding of the substrates proline and ATP and the inhibitor halofuginone. Acta Crystallogr.,Sect.D, 69:2136-2145, 2013 Cited by PubMed 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 2.4 Å 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. PubMed: 24100331DOI: 10.1107/S0907444913020556 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.619 Å) |
Structure validation
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