1pk0
From Proteopedia
Crystal Structure of the EF3-CaM complexed with PMEApp
Structural highlights
Function[CYAA_BACAN] One of the three proteins composing the anthrax toxin, the agent which infects many mammalian species and that may cause death. EF is a calmodulin-dependent adenylyl cyclase that, when associated with PA, causes edema. EF is not toxic by itself and it is required for the survival of germinated spores within macrophages at the early stages of infection. Provokes dramatic elevation of intracellular cAMP levels in the host. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedEdema factor (EF), a key virulence factor in anthrax pathogenesis, has calmodulin (CaM)-activated adenylyl cyclase activity. We have found that adefovir dipivoxil, a drug approved to treat chronic infection of hepatitis B virus, effectively inhibits EF-induced cAMP accumulation and changes in cytokine production in mouse primary macrophages. Adefovir diphosphate (PMEApp), the active cellular metabolite of adefovir dipivoxil, inhibits the adenylyl cyclase activity of EF in vitro with high affinity (K(i) = 27 nM). A crystal structure of EF-CaM-PMEApp reveals that the catalytic site of EF forms better van der Waals contacts and more hydrogen bonds with PMEApp than with its endogenous substrate, ATP, providing an explanation for the approximately 10,000-fold higher affinity EF-CaM has for PMEApp versus ATP. Adefovir dipivoxil is a clinically approved drug that can block the action of an anthrax toxin. It can be used to address the role of EF in anthrax pathogenesis. Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection.,Shen Y, Zhukovskaya NL, Zimmer MI, Soelaiman S, Bergson P, Wang CR, Gibbs CS, Tang WJ Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3242-7. Epub 2004 Feb 20. PMID:14978283[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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