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

2019; Wiley; Volume: 75; Issue: 9 Linguagem: Inglês

10.1107/s2053230x19010902

2053-230X

Sonja Schüssler, Ilka Haase, Markus Perbandt, Boris Illarionov, Alexandra Siemens, Klaus Richter, Adelbert Bacher, Markus Fischer, Tobias Gräwert,

Biochemical and Molecular Research

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 m = 53 µ M ; v max = 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 ( R free = 0.226) by molecular replacement using human GTP cyclohydrolase I as a template. The protein is a D 5 -symmetric decamer with ten topologically equivalent active sites. Screening a small library of about 9000 compounds afforded several inhibitors with IC 50 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.