Structure of GTP cyclohydrolase I from Listeria monocytogenes, a potential anti‐infective drug target. Issue 9 (2nd September 2019)

• Record Type: Journal Article
• Authors: Schüssler, Sonja; Haase, Ilka; Perbandt, Markus; Illarionov, Boris; Siemens, Alexandra; Richter, Klaus; Bacher, Adelbert; Fischer, Markus; Gräwert, Tobias
• Is Part Of: Acta crystallographica. Volume 75:Issue 9(2019:Sep.)
• Page Start: 586
• Page End: 592
• Publication Date: 2019-09-02
• Subjects: GTP cyclohydrolase I -- Listeria monocytogenes -- crystal structure -- high‐throughput screening -- tetrahydrofolate biosynthesis -- listeriosis; Crystallography -- Periodicals; Crystals -- Periodicals; 548
• DOI: 10.1107/S2053230X19010902
• Languages: English
• ISSNs: 2053-230X

Abstract

Abstract : GTP cyclohydrolase I from Listeria monocytogenes, a putative anti‐infective drug target, has been crystallized and the crystal structure was solved at 2.4 Å resolution. 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 ( 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 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.