8V9I
1-deoxy-D-xylulose 5-phosphate synthase (DXPS) from Deinococcus radiodurans with D-phenylalanine-derived triazole acetylphosphonate (D-PheTrAP) bound
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Summary for 8V9I
| Entry DOI | 10.2210/pdb8v9i/pdb |
| Descriptor | 1-deoxy-D-xylulose-5-phosphate synthase, 3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-2-{(1S)-1-[(S)-(2-{1-[(1R)-1-carboxy-2-phenylethyl]-1H-1,2,3-triazol-4-yl}ethoxy)(hydroxy)phosphoryl]-1-hydroxyethyl}-5-(2-{[(S)-hydroxy(phosphonooxy)phosphoryl]oxy}ethyl)-4-methyl-1,3-thiazol-3-ium, MAGNESIUM ION, ... (6 entities in total) |
| Functional Keywords | 1-deoxy-d-xylulose 5-phosphate synthase, dxps, thiamine diphosphate, thiamine pyrophosphate, thdp, tpp, the mep pathway, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Deinococcus radiodurans |
| Total number of polymer chains | 2 |
| Total formula weight | 141843.93 |
| Authors | |
| Primary citation | Coco, L.B.,Toci, E.M.,Chen, P.Y.,Drennan, C.L.,Freel Meyers, C.L. Potent Inhibition of E. coli DXP Synthase by a gem -Diaryl Bisubstrate Analog. Acs Infect Dis., 10:1312-1326, 2024 Cited by PubMed Abstract: New antimicrobial strategies are needed to address pathogen resistance to currently used antibiotics. Bacterial central metabolism is a promising target space for the development of agents that selectively target bacterial pathogens. 1-Deoxy-d-xylulose 5-phosphate synthase (DXPS) converts pyruvate and d-glyceraldehyde 3-phosphate (d-GAP) to DXP, which is required for synthesis of essential vitamins and isoprenoids in bacterial pathogens. Thus, DXPS is a promising antimicrobial target. Toward this goal, our lab has demonstrated selective inhibition of DXPS by alkyl acetylphosphonate (alkylAP)-based bisubstrate analogs that exploit the requirement for ternary complex formation in the DXPS mechanism. Here, we present the first DXPS structure with a bisubstrate analog bound in the active site. Insights gained from this cocrystal structure guided structure-activity relationship studies of the bisubstrate scaffold. A low nanomolar inhibitor (compound ) bearing a -dibenzyl glycine moiety conjugated to the acetylphosphonate pyruvate mimic via a triazole-based linker emerged from this study. Compound was found to exhibit slow, tight-binding inhibition, with contacts to DXPS residues R99 and R478 demonstrated to be important for this behavior. This work has discovered the most potent DXPS inhibitor to date and highlights a new role of R99 that can be exploited in future inhibitor designs toward the development of a novel class of antimicrobial agents. PubMed: 38513073DOI: 10.1021/acsinfecdis.3c00734 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.981 Å) |
Structure validation
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