5mu6

Human N-myristoyltransferase (NMT1) with Myristoyl-CoA and IMP-1088 inhibitor bound

spinqualitylabelsall models 5mu6, resolution 1.88Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5mu6 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.88Å Ligands: GOL, KFK, MG, MYA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NMT1_HUMAN Adds a myristoyl group to the N-terminal glycine residue of certain cellular and viral proteins. Publication Abstract from PubMed Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections. Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus.,Mousnier A, Bell AS, Swieboda DP, Morales-Sanfrutos J, Perez-Dorado I, Brannigan JA, Newman J, Ritzefeld M, Hutton JA, Guedan A, Asfor AS, Robinson SW, Hopkins-Navratilova I, Wilkinson AJ, Johnston SL, Leatherbarrow RJ, Tuthill TJ, Solari R, Tate EW Nat Chem. 2018 May 14. pii: 10.1038/s41557-018-0039-2. doi:, 10.1038/s41557-018-0039-2. PMID:29760414 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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