Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase

Leah S. Torrie; David A. Robinson; Michael G. Thomas; Judith V. Hobrath; Sharon M. Shepherd; John M. Post; Eun Jung Ko; Rafael Alves Ferreira; Claire J. Mackenzie; Karolina Wrobel; Darren P. Edwards; Ian H. Gilbert; David W. Gray; Alan H. Fairlamb; Manu De Rycker

doi:10.1021/acsinfecdis.9b00453

Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase

Leah S. Torrie, David A. Robinson, Michael G. Thomas, Judith V. Hobrath, Sharon M. Shepherd, John M. Post, Eun Jung Ko, Rafael Alves Ferreira, Claire J. Mackenzie, Karolina Wrobel, Darren P. Edwards, Ian H. Gilbert, David W. Gray (Lead / Corresponding author), Alan H. Fairlamb, Manu De Rycker (Lead / Corresponding author)

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Abstract

Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in kinetoplastid parasites Trypanosoma brucei and Leishmania donovani. To date, all kinetoplastid MetRS inhibitors described bind in a similar way to an expanded methionine pocket and an adjacent, auxiliary pocket. In the current study, we have identified a structurally novel class of inhibitors containing a 4,6-diamino-substituted pyrazolopyrimidine core (the MetRS02 series). Crystallographic studies revealed that MetRS02 compounds bind to an allosteric pocket in L. major MetRS not previously described, and enzymatic studies demonstrated a noncompetitive mode of inhibition. Homology modeling of the Trypanosoma cruzi MetRS enzyme revealed key differences in the allosteric pocket between the T. cruzi and Leishmania enzymes. These provide a likely explanation for the lower MetRS02 potencies that we observed for the T. cruzi enzyme compared to the Leishmania enzyme. The identification of a new series of MetRS inhibitors and the discovery of a new binding site in kinetoplastid MetRS enzymes provide a novel strategy in the search for new therapeutics for kinetoplastid diseases.

Original language	English
Pages (from-to)	1044-1057
Number of pages	14
Journal	ACS Infectious Diseases
Volume	6
Issue number	5
Early online date	10 Apr 2020
DOIs	https://doi.org/10.1021/acsinfecdis.9b00453
Publication status	Published - 8 May 2020

Keywords

allosteric
drug discovery
inhibitor
kinetoplastid
Leishmania
methionyl-tRNA synthetase

ASJC Scopus subject areas

Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1021/acsinfecdis.9b00453Licence: CC BY

Final published version
This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 5.32 MBLicence: CC BY

Cite this

Torrie, L. S., Robinson, D. A., Thomas, M. G., Hobrath, J. V., Shepherd, S. M., Post, J. M., Ko, E. J., Ferreira, R. A., Mackenzie, C. J., Wrobel, K., Edwards, D. P., Gilbert, I. H., Gray, D. W., Fairlamb, A. H., & De Rycker, M. (2020). Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase. ACS Infectious Diseases, 6(5), 1044-1057. https://doi.org/10.1021/acsinfecdis.9b00453

@article{010744f3dafd4d059800f15ea2a3c638,

title = "Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase",

abstract = "Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in kinetoplastid parasites Trypanosoma brucei and Leishmania donovani. To date, all kinetoplastid MetRS inhibitors described bind in a similar way to an expanded methionine pocket and an adjacent, auxiliary pocket. In the current study, we have identified a structurally novel class of inhibitors containing a 4,6-diamino-substituted pyrazolopyrimidine core (the MetRS02 series). Crystallographic studies revealed that MetRS02 compounds bind to an allosteric pocket in L. major MetRS not previously described, and enzymatic studies demonstrated a noncompetitive mode of inhibition. Homology modeling of the Trypanosoma cruzi MetRS enzyme revealed key differences in the allosteric pocket between the T. cruzi and Leishmania enzymes. These provide a likely explanation for the lower MetRS02 potencies that we observed for the T. cruzi enzyme compared to the Leishmania enzyme. The identification of a new series of MetRS inhibitors and the discovery of a new binding site in kinetoplastid MetRS enzymes provide a novel strategy in the search for new therapeutics for kinetoplastid diseases.",

keywords = "allosteric, drug discovery, inhibitor, kinetoplastid, Leishmania, methionyl-tRNA synthetase",

author = "Torrie, {Leah S.} and Robinson, {David A.} and Thomas, {Michael G.} and Hobrath, {Judith V.} and Shepherd, {Sharon M.} and Post, {John M.} and Ko, {Eun Jung} and Ferreira, {Rafael Alves} and Mackenzie, {Claire J.} and Karolina Wrobel and Edwards, {Darren P.} and Gilbert, {Ian H.} and Gray, {David W.} and Fairlamb, {Alan H.} and {De Rycker}, Manu",

note = "We acknowledge the Wellcome Trust for funding (grants 092340, 204672, and 203134)",

year = "2020",

month = may,

day = "8",

doi = "10.1021/acsinfecdis.9b00453",

language = "English",

volume = "6",

pages = "1044--1057",

journal = "ACS Infectious Diseases",

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publisher = "American Chemical Society",

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Torrie, LS, Robinson, DA, Thomas, MG, Hobrath, JV, Shepherd, SM, Post, JM, Ko, EJ, Ferreira, RA, Mackenzie, CJ, Wrobel, K, Edwards, DP , Gilbert, IH , Gray, DW , Fairlamb, AH & De Rycker, M 2020, 'Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase', ACS Infectious Diseases, vol. 6, no. 5, pp. 1044-1057. https://doi.org/10.1021/acsinfecdis.9b00453

TY - JOUR

T1 - Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase

AU - Torrie, Leah S.

AU - Robinson, David A.

AU - Thomas, Michael G.

AU - Hobrath, Judith V.

AU - Shepherd, Sharon M.

AU - Post, John M.

AU - Ko, Eun Jung

AU - Ferreira, Rafael Alves

AU - Mackenzie, Claire J.

AU - Wrobel, Karolina

AU - Edwards, Darren P.

AU - Gilbert, Ian H.

AU - Gray, David W.

AU - Fairlamb, Alan H.

AU - De Rycker, Manu

N1 - We acknowledge the Wellcome Trust for funding (grants 092340, 204672, and 203134)

PY - 2020/5/8

Y1 - 2020/5/8

N2 - Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in kinetoplastid parasites Trypanosoma brucei and Leishmania donovani. To date, all kinetoplastid MetRS inhibitors described bind in a similar way to an expanded methionine pocket and an adjacent, auxiliary pocket. In the current study, we have identified a structurally novel class of inhibitors containing a 4,6-diamino-substituted pyrazolopyrimidine core (the MetRS02 series). Crystallographic studies revealed that MetRS02 compounds bind to an allosteric pocket in L. major MetRS not previously described, and enzymatic studies demonstrated a noncompetitive mode of inhibition. Homology modeling of the Trypanosoma cruzi MetRS enzyme revealed key differences in the allosteric pocket between the T. cruzi and Leishmania enzymes. These provide a likely explanation for the lower MetRS02 potencies that we observed for the T. cruzi enzyme compared to the Leishmania enzyme. The identification of a new series of MetRS inhibitors and the discovery of a new binding site in kinetoplastid MetRS enzymes provide a novel strategy in the search for new therapeutics for kinetoplastid diseases.

AB - Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in kinetoplastid parasites Trypanosoma brucei and Leishmania donovani. To date, all kinetoplastid MetRS inhibitors described bind in a similar way to an expanded methionine pocket and an adjacent, auxiliary pocket. In the current study, we have identified a structurally novel class of inhibitors containing a 4,6-diamino-substituted pyrazolopyrimidine core (the MetRS02 series). Crystallographic studies revealed that MetRS02 compounds bind to an allosteric pocket in L. major MetRS not previously described, and enzymatic studies demonstrated a noncompetitive mode of inhibition. Homology modeling of the Trypanosoma cruzi MetRS enzyme revealed key differences in the allosteric pocket between the T. cruzi and Leishmania enzymes. These provide a likely explanation for the lower MetRS02 potencies that we observed for the T. cruzi enzyme compared to the Leishmania enzyme. The identification of a new series of MetRS inhibitors and the discovery of a new binding site in kinetoplastid MetRS enzymes provide a novel strategy in the search for new therapeutics for kinetoplastid diseases.

KW - allosteric

KW - drug discovery

KW - inhibitor

KW - kinetoplastid

KW - Leishmania

KW - methionyl-tRNA synthetase

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U2 - 10.1021/acsinfecdis.9b00453

DO - 10.1021/acsinfecdis.9b00453

M3 - Article

C2 - 32275825

AN - SCOPUS:85084722023

SN - 2373-8227

VL - 6

SP - 1044

EP - 1057

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

IS - 5

ER -

Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

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Wellcome Centre for Anti-Infectives Research

Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)

Cite this

Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Wellcome Centre for Anti-Infectives Research

Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)

Cite this