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Title: Structure determination of glycogen synthase kinase-3 from Leishmania major and comparative inhibitor structure-activity relationships with Trypanosoma brucei GSK-3

Abstract

Glycogen synthase kinase-3 (GSK-3) is a drug target under intense investigation in pharmaceutical companies and constitutes an attractive piggyback target for eukaryotic pathogens. Two different GSKs are found in trypanosomatids, one about 150 residues shorter than the other. GSK-3 short (GeneDB: Tb927.10.13780) has previously been validated genetically as a drug target in Trypanosoma brucei by RNAi induced growth retardation; and chemically by correlation between enzyme and in vitro growth inhibition. Here, we report investigation of the equivalent GSK-3 short enzymes of L. major (LmjF18.0270) and L. infantum (LinJ18_V3.0270, identical in amino acid sequences to LdonGSK-3 short) and a crystal structure of LmajGSK-3 short at 2 Å resolution. The inhibitor structure-activity relationships (SARs) of L. major and L. infantum are virtually identical, suggesting that inhibitors could be useful for both cutaneous and visceral leishmaniasis. Leishmania spp. GSK-3 short has different inhibitor SARs than TbruGSK-3 short, which can be explained mostly by two variant residues in the ATP-binding pocket. Indeed, mutating these residues in the ATP-binding site of LmajGSK-3 short to the TbruGSK-3 short equivalents results in a mutant LmajGSK-3 short enzyme with SAR more similar to that of TbruGSK-3 short. The differences between human GSK-3β (HsGSK-3β) and LmajGSK-3 short SAR suggestmore » that compounds which selectively inhibit LmajGSK-3 short may be found.« less

Authors:
; ; ; ; ; ; ; ; ;  [1]
  1. UWASH
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OTHERNIH
OSTI Identifier:
1037471
Resource Type:
Journal Article
Resource Relation:
Journal Name: Mol. Biochem. Parasit.; Journal Volume: 176; Journal Issue: (2) ; 04, 2011
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; AMINO ACID SEQUENCE; CRYSTAL STRUCTURE; DRUGS; ENZYMES; GLYCOGEN; GROWTH; IN VITRO; INHIBITION; MUTANTS; PATHOGENS; RESIDUES; RESOLUTION; STRUCTURE-ACTIVITY RELATIONSHIPS; TARGETS; TRYPANOSOMA

Citation Formats

Ojo, Kayode K, Arakaki, Tracy L, Napuli, Alberto J, Inampudi, Krishna K, Keyloun, Katelyn R, Zhang, Li, Hol, Wim G.J., Verlind, Christophe L.M.J., Merritt, Ethan A, and Van Voorhis, Wesley C. Structure determination of glycogen synthase kinase-3 from Leishmania major and comparative inhibitor structure-activity relationships with Trypanosoma brucei GSK-3. United States: N. p., 2012. Web. doi:10.1016/j.molbiopara.2010.12.009.
Ojo, Kayode K, Arakaki, Tracy L, Napuli, Alberto J, Inampudi, Krishna K, Keyloun, Katelyn R, Zhang, Li, Hol, Wim G.J., Verlind, Christophe L.M.J., Merritt, Ethan A, & Van Voorhis, Wesley C. Structure determination of glycogen synthase kinase-3 from Leishmania major and comparative inhibitor structure-activity relationships with Trypanosoma brucei GSK-3. United States. doi:10.1016/j.molbiopara.2010.12.009.
Ojo, Kayode K, Arakaki, Tracy L, Napuli, Alberto J, Inampudi, Krishna K, Keyloun, Katelyn R, Zhang, Li, Hol, Wim G.J., Verlind, Christophe L.M.J., Merritt, Ethan A, and Van Voorhis, Wesley C. Tue . "Structure determination of glycogen synthase kinase-3 from Leishmania major and comparative inhibitor structure-activity relationships with Trypanosoma brucei GSK-3". United States. doi:10.1016/j.molbiopara.2010.12.009.
@article{osti_1037471,
title = {Structure determination of glycogen synthase kinase-3 from Leishmania major and comparative inhibitor structure-activity relationships with Trypanosoma brucei GSK-3},
author = {Ojo, Kayode K and Arakaki, Tracy L and Napuli, Alberto J and Inampudi, Krishna K and Keyloun, Katelyn R and Zhang, Li and Hol, Wim G.J. and Verlind, Christophe L.M.J. and Merritt, Ethan A and Van Voorhis, Wesley C},
abstractNote = {Glycogen synthase kinase-3 (GSK-3) is a drug target under intense investigation in pharmaceutical companies and constitutes an attractive piggyback target for eukaryotic pathogens. Two different GSKs are found in trypanosomatids, one about 150 residues shorter than the other. GSK-3 short (GeneDB: Tb927.10.13780) has previously been validated genetically as a drug target in Trypanosoma brucei by RNAi induced growth retardation; and chemically by correlation between enzyme and in vitro growth inhibition. Here, we report investigation of the equivalent GSK-3 short enzymes of L. major (LmjF18.0270) and L. infantum (LinJ18_V3.0270, identical in amino acid sequences to LdonGSK-3 short) and a crystal structure of LmajGSK-3 short at 2 Å resolution. The inhibitor structure-activity relationships (SARs) of L. major and L. infantum are virtually identical, suggesting that inhibitors could be useful for both cutaneous and visceral leishmaniasis. Leishmania spp. GSK-3 short has different inhibitor SARs than TbruGSK-3 short, which can be explained mostly by two variant residues in the ATP-binding pocket. Indeed, mutating these residues in the ATP-binding site of LmajGSK-3 short to the TbruGSK-3 short equivalents results in a mutant LmajGSK-3 short enzyme with SAR more similar to that of TbruGSK-3 short. The differences between human GSK-3β (HsGSK-3β) and LmajGSK-3 short SAR suggest that compounds which selectively inhibit LmajGSK-3 short may be found.},
doi = {10.1016/j.molbiopara.2010.12.009},
journal = {Mol. Biochem. Parasit.},
number = (2) ; 04, 2011,
volume = 176,
place = {United States},
year = {Tue Apr 24 00:00:00 EDT 2012},
month = {Tue Apr 24 00:00:00 EDT 2012}
}