6ezj

Imidazoleglycerol-phosphate dehydratase

spinqualitylabelsall models 6ezj, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ezj is a 24 chain structure with sequence from Arath. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 5LD, MN Gene: HISN5B, At4g14910, dl3495c (ARATH) Activity: Imidazoleglycerol-phosphate dehydratase, with EC number 4.2.1.19 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Histidine biosynthesis is an essential process in plants and microorganisms, making it an attractive target for the development of herbicides and antibacterial agents. Imidazoleglycerol-phosphate dehydratase (IGPD), a key enzyme within this pathway, has been biochemically characterized in both Saccharomyces cerevisiae (Sc_IGPD) and Arabidopsis thaliana (At_IGPD). The plant enzyme, having been the focus of in-depth structural analysis as part of an inhibitor development program, has revealed details about the reaction mechanism of IGPD, whereas the yeast enzyme has proven intractable to crystallography studies. The structure-activity relationship of potent triazole-phosphonate inhibitors of IGPD has been determined in both homologs, revealing that the lead inhibitor (C348) is an order of magnitude more potent against Sc_IGPD than At_IGPD; however, the molecular basis of this difference has not been established. Here we have used single-particle electron microscopy (EM) to study structural differences between the At and Sc_IGPD homologs, which could influence the difference in inhibitor potency. The resulting EM maps at approximately 3 A are sufficient to de novo build the protein structure and identify the inhibitor binding site, which has been validated against the crystal structure of the At_IGPD/C348 complex. The structure of Sc_IGPD reveals that a 24-amino acid insertion forms an extended loop region on the enzyme surface that lies adjacent to the active site, forming interactions with the substrate/inhibitor binding loop that may influence inhibitor potency. Overall, this study provides insights into the IGPD family and demonstrates the power of using an EM approach to study inhibitor binding. Elucidating the structural basis for differing enzyme inhibitor potency by cryo-EM.,Rawson S, Bisson C, Hurdiss DL, Fazal A, McPhillie MJ, Sedelnikova SE, Baker PJ, Rice DW, Muench SP Proc Natl Acad Sci U S A. 2018 Feb 6. pii: 1708839115. doi:, 10.1073/pnas.1708839115. PMID:29434040 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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