4ae1

Crystal structure of diphtheria toxin mutant CRM197 in complex with nicotinamide

spinqualitylabelsall models 4ae1, resolution 2.08Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ae1 is a 2 chain structure with sequence from Corynebacterium diphtheriae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NCA Related: 4ae0, 1f0l, 1sgk, 1dtp, 1ddt, 1mdt, 1tox, 1xdt Activity: NAD(+)--diphthamide ADP-ribosyltransferase, with EC number 2.4.2.36 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [DTX_CORBE] Diphtheria toxin, produced by a phage infecting Corynebacterium diphtheriae, is a proenzyme that, after activation, catalyzes the covalent attachment of the ADP ribose moiety of NAD to eukaryotic elongation factor 2 (eEF-2). Fragment A is the catalytic portion responsible for enzymatic ADP-ribosylation of elongation factor 2, while fragment B is responsible for binding of toxin to cell receptors and entry of fragment A. Publication Abstract from PubMed CRM197 is an enzymatically inactive and nontoxic form of diphtheria toxin that contains a single amino acid substitution (G52E). Being naturally nontoxic, CRM197 is an ideal carrier protein for conjugate vaccines against encapsulated bacteria and is currently used to vaccinate children globally against Haemophilus influenzae, pneumococcus, and meningococcus. To understand the molecular basis for lack of toxicity in CRM197, we determined the crystal structures of the full-length nucleotide-free CRM197 and of CRM197 in complex with the NAD hydrolysis product nicotinamide (NCA), both at 2.0-A resolution. The structures show for the first time that the overall fold of CRM197 and DT are nearly identical and that the striking functional difference between the two proteins can be explained by a flexible active-site loop that covers the NAD binding pocket. We present the molecular basis for the increased flexibility of the active-site loop in CRM197 as unveiled by molecular dynamics simulations. These structural insights, combined with surface plasmon resonance, NAD hydrolysis, and differential scanning fluorimetry data, contribute to a comprehensive characterization of the vaccine carrier protein, CRM197. Structural basis for lack of toxicity of the diphtheria toxin mutant CRM197.,Malito E, Bursulaya B, Chen C, Surdo PL, Picchianti M, Balducci E, Biancucci M, Brock A, Berti F, Bottomley MJ, Nissum M, Costantino P, Rappuoli R, Spraggon G Proc Natl Acad Sci U S A. 2012 Mar 19. PMID:22431623 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Diphtheria toxin

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