6ppx

Crystal structure of metal-free NeuB, an N-acetylneuraminate synthase from Neisseria meningitidis in complex with malate

spinqualitylabelsall models 6ppx, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ppx is a 1 chain structure with sequence from Neisseria meningitidis serogroup B. This structure supersedes the now removed PDB entry 3cm4. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.85Å Ligands: MLT Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function H2VFG5_NEIMI Publication Abstract from PubMed NeuB is a bacterial sialic acid synthase used by neuroinvasive bacteria to synthesize <i>N</i>-acetylneuraminate (NeuNAc), helping them to evade the host immune system. NeuNAc oxime is a potent slow-binding NeuB inhibitor. It dissociated too slowly to be detected experimentally, with initial estimates of its residence time in the active site being > 47 days. This is longer than the lifetime of a typical bacterial cell, meaning that inhibition is effectively irreversible. Inhibition data fitted well to a model that included a pre-equilibration step with <i>K</i><sub>i</sub> = 36 muM, followed by effectively irreversible conversion to an E*.I complex, with <i>k</i><sub>2<\sub> = 5.6 x 10<sup>-5</sup> s<sup>-1</sup>. Thus, the inhibitor is able to subvert ligand release and achieve extraordinary residence times in spite of a relatively modest initial dissociation constant. The crystal structure showed the oxime functional group occupying the phosphate binding site normally occupied by the substrate PEP and the tetrahedral intermediate. There was a ~10% residual rate at high inhibitor concentrations regardless of how long NeuB and NeuNAc oxime were pre-incubated together. However, complete inhibition was achieved by incubating NeuNAc oxime with actively catalyzing enzyme. This requirement for the enzyme to be actively turning over in order for the inhibitor to bind to the second subunit demonstrated an important role for inter-subunit communication in the inhibitory mechanism. NeuNAc oxime: A slow-binding and effectively irreversible inhibitor of the sialic acid synthase NeuB.,Popovic V, Morrison E, Rosanally AZ, Balachandran N, Senson AW, Szabla R, Junop MS, Berti PJ Biochemistry. 2019 Sep 24. doi: 10.1021/acs.biochem.9b00654. PMID:31549502 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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