TY - JOUR
T1 - Conformational heterogeneity in apo and drug-bound structures of Toxoplasma gondii prolyl-tRNA synthetase
AU - Mishra, Siddhartha
AU - Malhotra, Nipun
AU - Kumari, Shreya
AU - Sato, Mizuki
AU - Kikuchi, Haruhisa
AU - Yogavel, Manickam
AU - Sharma, Amit
N1 - Funding Information:
The following funding is acknowledged: Department of Biotechnology, Ministry of Science and Technology (grant No. PR6303 to Amit Sharma; grant No. PR13636 to Amit Sharma and Manickam Yogavel); Indo-French Centre for the Promotion of Advanced Research (IFCPAR/CEFIPRA; Travel Grant to Manickam Yogavel); Department of Science and Technology, India (award No. SB/S2/JCB-41/2013 to Amit Sharma).
Publisher Copyright:
© 2019 International Union of Crystallography.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase family that drives protein translation in cells. The apicomplexan PRSs are validated targets of febrifugine (FF) and its halogenated derivative halofuginone (HF). PRSs are of great interest for drug development against Plasmodium falciparum and Toxoplasma gondii. In this study, structures of apo and FF-bound T. gondii (TgPRS) are revealed and the dynamic nature of the conformational changes that occur upon FF binding is unraveled. In addition, this study highlights significant conformational plasticity within two different crystal structures of apo PRSs but not within drug-bound PRSs. The apo PRSs exist in multi-conformational states and manifest pseudo-dimeric structures. In contrast, when FF is bound the PRS dimer adopts a highly symmetrical architecture. It is shown that TgPRS does not display extant fold switching, in contrast to P. falciparum PRS, despite having over 65% sequence identity. Finally, structure-comparison analyses suggest the utility of r.m.s.d. per residue (r.m.s.d./res) as a robust tool to detect structural alterations even when the r.m.s.d. is low. Apo TgPRS reveals FF/HF-induced rigidity and this work has implications for drug-design studies that rely on the apo structures of target proteins.
AB - Prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase family that drives protein translation in cells. The apicomplexan PRSs are validated targets of febrifugine (FF) and its halogenated derivative halofuginone (HF). PRSs are of great interest for drug development against Plasmodium falciparum and Toxoplasma gondii. In this study, structures of apo and FF-bound T. gondii (TgPRS) are revealed and the dynamic nature of the conformational changes that occur upon FF binding is unraveled. In addition, this study highlights significant conformational plasticity within two different crystal structures of apo PRSs but not within drug-bound PRSs. The apo PRSs exist in multi-conformational states and manifest pseudo-dimeric structures. In contrast, when FF is bound the PRS dimer adopts a highly symmetrical architecture. It is shown that TgPRS does not display extant fold switching, in contrast to P. falciparum PRS, despite having over 65% sequence identity. Finally, structure-comparison analyses suggest the utility of r.m.s.d. per residue (r.m.s.d./res) as a robust tool to detect structural alterations even when the r.m.s.d. is low. Apo TgPRS reveals FF/HF-induced rigidity and this work has implications for drug-design studies that rely on the apo structures of target proteins.
KW - apo-holo transistions
KW - comparative crystallography
KW - drug design
KW - enzyme-inhibitor complexes
KW - prolyl-tRNA synthetase
KW - r.m.s.d. per residue profile
KW - toxoplasmosis
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U2 - 10.1107/S2053230X19014808
DO - 10.1107/S2053230X19014808
M3 - Article
C2 - 31702585
AN - SCOPUS:85074687600
SN - 1744-3091
VL - 75
SP - 714
EP - 724
JO - Acta Crystallographica Section F:Structural Biology Communications
JF - Acta Crystallographica Section F:Structural Biology Communications
ER -