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| ==Overview==
| | {{ABSTRACT_7833808}} |
| The structure of toxic monomeric diphtheria toxin (DT) was determined at 2.3 A resolution by molecular replacement based on the domain structures in dimeric DT and refined to an R factor of 20.7%. The model consists of 2 monomers in the asymmetric unit (1,046 amino acid residues), including 2 bound adenylyl 3'-5' uridine 3' monophosphate molecules and 396 water molecules. The structures of the 3 domains are virtually identical in monomeric and dimeric DT; however, monomeric DT is compact and globular as compared to the "open" monomer within dimeric DT (Bennett MJ, Choe S, Eisenberg D, 1994b, Protein Sci 3:0000-0000). Detailed differences between monomeric and dimeric DT are described, particularly (1) changes in main-chain conformations of 8 residues acting as a hinge to "open" or "close" the receptor-binding (R) domain, and (2) a possible receptor-docking site, a beta-hairpin loop protruding from the R domain containing residues that bind the cell-surface DT receptor. Based on the monomeric and dimeric DT crystal structures we have determined and the solution studies of others, we present a 5-step structure-based mechanism of intoxication: (1) proteolysis of a disulfide-linked surface loop (residues 186-201) between the catalytic (C) and transmembrane (T) domains; (2) binding of a beta-hairpin loop protruding from the R domain to the DT receptor, leading to receptor-mediated endocytosis; (3) low pH-triggered open monomer formation and exposure of apolar surfaces in the T domain, which insert into the endosomal membrane; (4) translocation of the C domain into the cytosol; and (5) catalysis by the C domain of ADP-ribosylation of elongation factor 2.
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| ==About this Structure== | | ==About this Structure== |
| 1MDT is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Corynephage_beta Corynephage beta]. The following page contains interesting information on the relation of 1MDT with [[http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb69_1.html Cholera Toxin]]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MDT OCA]. | | 1MDT is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Corynephage_beta Corynephage beta]. The following page contains interesting information on the relation of 1MDT with [[http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb69_1.html Cholera Toxin]]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MDT OCA]. |
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| ==Reference==
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| Refined structure of monomeric diphtheria toxin at 2.3 A resolution., Bennett MJ, Eisenberg D, Protein Sci. 1994 Sep;3(9):1464-75. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/7833808 7833808]
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| [[Category: Cholera Toxin]] | | [[Category: Cholera Toxin]] |
| [[Category: Corynephage beta]] | | [[Category: Corynephage beta]] |
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| [[Category: Eisenberg, D.]] | | [[Category: Eisenberg, D.]] |
| [[Category: Toxin]] | | [[Category: Toxin]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 00:55:21 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Jun 26 17:42:36 2008'' |
