6da0 | pdb_00006da0

Crystal structure of glucokinase (NfHK) from Naegleria fowleri

spinqualitylabelsall models 6da0, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6da0 is a 1 chain structure with sequence from Naegleria fowleri. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.2Å Ligands: ANP, BGC Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A384E136_NAEFO Publication Abstract from PubMed Infection with the free-living amoeba Naegleria fowleri leads to life-threatening primary amoebic meningoencephalitis. Efficacious treatment options for these infections are limited, and the mortality rate is very high ( approximately 98%). Parasite metabolism may provide suitable targets for therapeutic design. Like most other organisms, glucose metabolism is critical for parasite viability, being required for growth in culture. The first enzyme required for glucose metabolism is typically a hexokinase (HK), which transfers a phosphate from ATP to glucose. The products of this enzyme are required for both glycolysis and the pentose phosphate pathway. However, the N. fowleri genome lacks an obvious HK homolog and instead harbors a glucokinase (Glck). The N. fowleri Glck (NfGlck) shares limited (25%) amino acid identity with the mammalian host enzyme (Homo sapiens Glck), suggesting that parasite-specific inhibitors with anti-amoeba activity can be generated. Following heterologous expression, NfGlck was found to have a limited hexose substrate range, with the greatest activity observed with glucose. The enzyme had apparent Km values of 42.5 +/- 7.3 muM and 141.6 +/- 9.9 muM for glucose and ATP, respectively. The NfGlck structure was determined and refined to 2.2-A resolution, revealing that the enzyme shares greatest structural similarity with the Trypanosoma cruzi Glck. These similarities include binding modes and binding environments for substrates. To identify inhibitors of NfGlck, we screened a small collection of inhibitors of glucose-phosphorylating enzymes and identified several small molecules with 50% inhibitory concentration values of <1 muM that may prove useful as hit chemotypes for further leads and therapeutic development against N. fowleri. Enzymatic and Structural Characterization of the Naegleria fowleri Glucokinase.,Milanes JE, Suryadi J, Abendroth J, Van Voorhis WC, Barrett KF, Dranow DM, Phan IQ, Patrick SL, Rozema SD, Khalifa MM, Golden JE, Morris JC Antimicrob Agents Chemother. 2019 Apr 25;63(5). pii: AAC.02410-18. doi:, 10.1128/AAC.02410-18. Print 2019 May. PMID:30783001 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Hexokinase 3D structures

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