8qj8

Structure of Mycobacterium abscessus Phosphopantetheine adenylyltransferase in complex with inhibitor

spinqualitylabelsall models 8qj8, resolution 1.54Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8qj8 is a 3 chain structure with sequence from Mycobacteroides abscessus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.538Å Ligands: VIW Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function COAD_MYCA9 Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate. Publication Abstract from PubMed Ligand binding hotspots are regions of protein surfaces that form particularly favourable interactions with small molecule pharmacophores. Targeting interactions with these hotspots maximises the efficiency of ligand binding. Existing methods are capable of identifying hotspots but often lack assays to quantify ligand binding and direct elaboration at these sites. Herein, we describe a fragment-based competitive 19F Ligand Based-NMR (LB-NMR) screening platform that enables routine, quantitative ligand profiling focused at ligand-binding hotspots. As a proof of concept, the method was applied to 4'-phosphopantetheine adenylyltransferase (PPAT) from Mycobacterium abscessus (Mabs). X-ray crystallographic characterisation of the hits from a 960-member fragment screen identified three ligand-binding hotspots across the PPAT active site. From the fragment hits a collection of 19F reporter candidates were designed and synthesised. By rigorous prioritisation and use of optimisation workflows, a single 19F reporter molecule was generated for each hotspot. Profiling the binding of a set of structurally characterised ligands by competitive 19F LB-NMR with this suite of 19F reporters recapitulated the binding affinity and site ID assignments made by ITC and X-ray crystallography. This quantitative mapping of ligand binding events at hotspot level resolution establishes the utility of the fragment-based competitive 19F LB-NMR screening platform for hotspot-directed ligand profiling. A fragment based competitive 19F LB-NMR platform for hotspot directed ligand profiling.,McCarthy WJ, Thomas SE, Olaleye T, Boland JA, Floto RA, Williams G, Blundell TL, Coyne AG, Abell C Angew Chem Int Ed Engl. 2024 Jun 19:e202406846. doi: 10.1002/anie.202406846. PMID:38896426 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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