5ko1 | pdb_00005ko1

Pseudokinase Domain of MLKL bound to Compound 4.

spinqualitylabelsall models 5ko1, resolution 2.16Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ko1 is a 1 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 2.16Å Ligands: 6UY Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MLKL_HUMAN Required for the execution of programmed necrosis. Publication Abstract from PubMed MLKL is a pore forming pseudokinase involved in the final stage of necroptosis, a form of programmed cell death. Its phosphorylation by RIPK3 is necessary for triggering necroptosis but not for triggering apoptosis, which makes it a unique target for pharmacological inhibition to block necroptotic cell death. This mechanism has been described as playing a role in disease progression in neurodegenerative and inflammatory diseases. A type II kinase inhibitor (cpd 1) has been described that reportedly binds to the MLKL pseudokinase domain and prevents necroptosis. Here we describe five compounds that bind to the MLKL ATP-binding site, however the four MLKL-selective compounds have no activity in rescuing cells from necroptosis. We use kinase selectivity panels, crystallography and a new conformationally sensitive method of measuring protein conformational changes (SHG) to confirm that the one previously reported compound that can rescue cells (cpd 1) is a non-selective type II inhibitor that also inhibits the upstream kinase RIPK1. Although this compound can shift the GFE motif of the activation loop to an "out" position, the accessibility of the key residue Ser358 in the MLKL activation loop is not affected by compound binding to the MLKL active site. Our studies indicate that an ATP-pocket inhibitor of the MLKL pseudokinase domain does not have any impact on the necroptosis pathway, which is contrary to a previously reported study. ATP-Competitive MLKL Binders Have No Functional Impact on Necroptosis.,Ma B, Marcotte D, Paramasivam M, Michelsen K, Wang T, Bertolotti-Ciarlet A, Jones JH, Moree B, Butko M, Salafsky J, Sun X, McKee T, Silvian LF PLoS One. 2016 Nov 10;11(11):e0165983. doi: 10.1371/journal.pone.0165983., eCollection 2016. PMID:27832137 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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