9b71 | pdb_00009b71

Cryo-EM structure of MraY in complex with analogue 3

spinqualitylabelsall models 9b71, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9b71 is a 4 chain structure with sequence from Aquifex aeolicus VF5 and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.7Å Ligands: A1AI2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MRAY_AQUAE First step of the lipid cycle reactions in the biosynthesis of the cell wall peptidoglycan (By similarity). Publication Abstract from PubMed MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities. Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target.,Yamamoto K, Sato T, Hao A, Asao K, Kaguchi R, Kusaka S, Ruddarraju RR, Kazamori D, Seo K, Takahashi S, Horiuchi M, Yokota SI, Lee SY, Ichikawa S Nat Commun. 2024 Jun 14;15(1):5085. doi: 10.1038/s41467-024-49484-7. PMID:38877016 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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