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Structure of GTP cyclohydrolase I from Listeria monocytogenes, a potential anti-infective drug target.


ABSTRACT: A putative open reading frame encoding GTP cyclohydrolase I from Listeria monocytogenes was expressed in a recombinant Escherichia coli strain. The recombinant protein was purified and was confirmed to convert GTP to dihydroneopterin triphosphate (Km = 53?µM; vmax = 180?nmol?mg-1?min-1). The protein was crystallized from 1.3?M sodium citrate pH 7.3 and the crystal structure was solved at a resolution of 2.4?Å (Rfree = 0.226) by molecular replacement using human GTP cyclohydrolase I as a template. The protein is a D5-symmetric decamer with ten topologically equivalent active sites. Screening a small library of about 9000 compounds afforded several inhibitors with IC50 values in the low-micromolar range. Several inhibitors had significant selectivity with regard to human GTP cyclohydrolase I. Hence, GTP cyclohydrolase I may be a potential target for novel drugs directed at microbial infections, including listeriosis, a rare disease with high mortality.

SUBMITTER: Schussler S 

PROVIDER: S-EPMC6718149 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Structure of GTP cyclohydrolase I from Listeria monocytogenes, a potential anti-infective drug target.

Schüssler Sonja S   Haase Ilka I   Perbandt Markus M   Illarionov Boris B   Siemens Alexandra A   Richter Klaus K   Bacher Adelbert A   Fischer Markus M   Gräwert Tobias T  

Acta crystallographica. Section F, Structural biology communications 20190830 Pt 9


A putative open reading frame encoding GTP cyclohydrolase I from Listeria monocytogenes was expressed in a recombinant Escherichia coli strain. The recombinant protein was purified and was confirmed to convert GTP to dihydroneopterin triphosphate (K<sub>m</sub> = 53 µM; v<sub>max</sub> = 180 nmol mg<sup>-1</sup> min<sup>-1</sup>). The protein was crystallized from 1.3 M sodium citrate pH 7.3 and the crystal structure was solved at a resolution of 2.4 Å (R<sub>free</sub> = 0.226) by molecular rep  ...[more]

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