1pk0
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Edema factor (EF), a key virulence factor in anthrax pathogenesis, has | + | Edema 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. |
==Disease== | ==Disease== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Shen, Y.]] | [[Category: Shen, Y.]] | ||
| - | [[Category: Tang, W | + | [[Category: Tang, W J.]] |
[[Category: CA]] | [[Category: CA]] | ||
[[Category: EMA]] | [[Category: EMA]] | ||
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[[Category: prodrug complex]] | [[Category: prodrug complex]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:29:38 2008'' |
Revision as of 12:29, 21 February 2008
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Crystal Structure of the EF3-CaM complexed with PMEApp
Contents |
Overview
Edema 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.
Disease
Known diseases associated with this structure: Cavernous malformations of CNS and retina OMIM:[604214], Cerebral cavernous malformations-1 OMIM:[604214], Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations OMIM:[604214], Leukemia, acute T-cell lymphoblastic OMIM:[603025], Leukemia, acute myeloid OMIM:[603025]
About this Structure
1PK0 is a Protein complex structure of sequences from Bacillus anthracis and Homo sapiens with , and as ligands. Active as Adenylate cyclase, with EC number 4.6.1.1 Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Thu Feb 21 14:29:38 2008
Categories: Adenylate cyclase | Bacillus anthracis | Homo sapiens | Protein complex | Shen, Y. | Tang, W J. | CA | EMA | YB | Cam | Edema factor | Prodrug complex
