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Crystal structures of three protozoan homologs of tryptophanyl-tRNA synthetase.

Merritt EA, Arakaki TL, Gillespie R, Napuli AJ, Kim JE, Buckner FS, Van Voorhis WC, Verlinde CL, Fan E, Zucker F, Hol WG
Mol Biochem Parasitol 177 20-8 (2011)
Related entries: 3hzr, 3i05

Cited: 11 times
EuropePMC logo PMID: 21255615

Abstract

Tryptophanyl-tRNA synthetase (TrpRS) is an essential enzyme that is recognizably conserved across all forms of life. It is responsible for activating and attaching tryptophan to a cognate tRNA(Trp) molecule for use in protein synthesis. In some eukaryotes this original core function has been supplemented or modified through the addition of extra domains or the expression of variant TrpRS isoforms. The three TrpRS structures from pathogenic protozoa described here represent three illustrations of this malleability in eukaryotes. The Cryptosporidium parvum genome contains a single TrpRS gene, which codes for an N-terminal domain of uncertain function in addition to the conserved core TrpRS domains. Sequence analysis indicates that this extra domain, conserved among several apicomplexans, is related to the editing domain of some AlaRS and ThrRS. The C. parvum enzyme remains fully active in charging tRNA(Trp) after truncation of this extra domain. The crystal structure of the active, truncated enzyme is presented here at 2.4Å resolution. The Trypanosoma brucei genome contains separate cytosolic and mitochondrial isoforms of TrpRS that have diverged in their respective tRNA recognition domains. The crystal structure of the T. brucei cytosolic isoform is presented here at 2.8Å resolution. The Entamoeba histolytica genome contains three sequences that appear to be TrpRS homologs. However one of these, whose structure is presented here at 3.0Å resolution, has lost the active site motifs characteristic of the Class I aminoacyl-tRNA synthetase catalytic domain while retaining the conserved features of a fully formed tRNA(Trp) recognition domain. The biological function of this variant E. histolytica TrpRS remains unknown, but, on the basis of a completely conserved tRNA recognition region and evidence for ATP but not tryptophan binding, it is tempting to speculate that it may perform an editing function. Together with a previously reported structure of an unusual TrpRS from Giardia, these protozoan structures broaden our perspective on the extent of structural variation found in eukaryotic TrpRS homologs.

Articles - 3hv0 mentioned but not cited (2)

  1. An appended domain results in an unusual architecture for malaria parasite tryptophanyl-tRNA synthetase. Khan S, Garg A, Sharma A, Camacho N, Picchioni D, Saint-Léger A, Ribas de Pouplana L, Yogavel M, Sharma A. PLoS One 8 e66224 (2013)
  2. Crystal structures of three protozoan homologs of tryptophanyl-tRNA synthetase. Merritt EA, Arakaki TL, Gillespie R, Napuli AJ, Kim JE, Buckner FS, Van Voorhis WC, Verlinde CL, Fan E, Zucker F, Hol WG. Mol Biochem Parasitol 177 20-28 (2011)


Reviews citing this publication (5)

  1. Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites. Pham JS, Dawson KL, Jackson KE, Lim EE, Pasaje CF, Turner KE, Ralph SA. Int J Parasitol Drugs Drug Resist 4 1-13 (2014)
  2. Emergence and evolution. Bullwinkle TJ, Ibba M. Top Curr Chem 344 43-87 (2014)
  3. The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations. Ogungbe IV, Setzer WN. Molecules 21 E1389 (2016)
  4. Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites. Nasim F, Qureshi IA. ACS Omega 8 14884-14899 (2023)
  5. Exploration of aminoacyl-tRNA synthetases from eukaryotic parasites for drug development. Gill J, Sharma A. J Biol Chem 299 102860 (2023)

Articles citing this publication (4)

  1. Crystal structures of Plasmodium falciparum cytosolic tryptophanyl-tRNA synthetase and its potential as a target for structure-guided drug design. Koh CY, Kim JE, Napoli AJ, Verlinde CL, Fan E, Buckner FS, Van Voorhis WC, Hol WG. Mol Biochem Parasitol 189 26-32 (2013)
  2. Genetic validation of aminoacyl-tRNA synthetases as drug targets in Trypanosoma brucei. Kalidas S, Cestari I, Monnerat S, Li Q, Regmi S, Hasle N, Labaied M, Parsons M, Stuart K, Phillips MA. Eukaryot Cell 13 504-516 (2014)
  3. Ligand co-crystallization of aminoacyl-tRNA synthetases from infectious disease organisms. Moen SO, Edwards TE, Dranow DM, Clifton MC, Sankaran B, Van Voorhis WC, Sharma A, Manoil C, Staker BL, Myler PJ, Lorimer DD. Sci Rep 7 223 (2017)
  4. Crystal structures of Entamoeba histolytica lysyl-tRNA synthetase reveal conformational changes upon lysine binding and a specific helix bundle domain. Bonnefond L, Castro de Moura M, Ribas de Pouplana L, Nureki O. FEBS Lett 588 4478-4486 (2014)


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