Structure of GTP cyclohydrolase I from Listeria monocytogenes, a potential anti-infective drug target
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 µ M; 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.
Source: Acta Crystallographica Section F - Category: Biochemistry Authors: Sch ü ssler, S. Haase, I. Perbandt, M. Illarionov, B. Siemens, A. Richter, K. Bacher, A. Fischer, M. Gr ä wert, T. Tags: GTP cyclohydrolase I Listeria monocytogenes crystal structure high-throughput screening tetrahydrofolate biosynthesis listeriosis research communications Source Type: research
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