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9GCA

Crystal structure of Pseudomonas aeruginosa IspD in complex with C8H8N2O

This is a non-PDB format compatible entry.
Summary for 9GCA
Entry DOI10.2210/pdb9gca/pdb
Descriptor2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase, 6-methyl-5~{H}-pyrrolo[3,4-b]pyridin-7-one (3 entities in total)
Functional Keywordstransferase, cytidylyltransferase, mep, isoprenoid biosynthesys, ispd, pseudomonas aeruginosa
Biological sourcePseudomonas aeruginosa
Total number of polymer chains1
Total formula weight28207.05
Authors
Borel, F.,D'Auria, L. (deposition date: 2024-08-01, release date: 2025-06-11)
Primary citationWillocx, D.,D'Auria, L.,Walsh, D.,Scherer, H.,Alhayek, A.,Hamed, M.M.,Borel, F.,Diamanti, E.,Hirsch, A.K.H.
Fragment Discovery by X-Ray Crystallographic Screening Targeting the CTP Binding Site of Pseudomonas Aeruginosa IspD.
Angew.Chem.Int.Ed.Engl., 64:e202414615-e202414615, 2025
Cited by
PubMed Abstract: With antimicrobial resistance (AMR) reaching alarming levels, new anti-infectives with unprecedented mechanisms of action are urgently needed. The 2-C-methylerythritol-D-erythritol-4-phosphate (MEP) pathway represents an attractive source of drug targets due to its essential role in numerous pathogenic Gram-negative bacteria and Mycobacterium tuberculosis (Mt), whilst being absent in human cells. Here, we solved the first crystal structure of Pseudomonas aeruginosa (Pa) IspD, the third enzyme in the MEP pathway and present the discovery of a fragment-based compound class identified through crystallographic screening of PaIspD. The initial fragment occupies the CTP binding cavity within the active site. Confirmation of fragment-protein interactions was achieved through H saturation-transfer difference nuclear magnetic resonance (H-STD NMR spectroscopy). Building upon these findings and insights from the co-crystal structures, we identified two growth vectors for fragment growing. We synthesized derivatives addressing both growth vectors, which showed improved affinities for PaIspD. Our new fragment class targets PaIspD, displays promising affinity and favorable growth vectors for further optimization.
PubMed: 39676054
DOI: 10.1002/anie.202414615
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.17 Å)
Structure validation

238895

数据于2025-07-16公开中

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