1pk0
From Proteopedia
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|PDB= 1pk0 |SIZE=350|CAPTION= <scene name='initialview01'>1pk0</scene>, resolution 3.30Å | |PDB= 1pk0 |SIZE=350|CAPTION= <scene name='initialview01'>1pk0</scene>, resolution 3.30Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand= | + | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EMA:(ADENIN-9-YL-ETHOXYMETHYL)-HYDROXYPHOSPHINYL-DIPHOSPHATE'>EMA</scene>, <scene name='pdbligand=YB:YTTERBIUM+(III)+ION'>YB</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Adenylate_cyclase Adenylate cyclase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.1 4.6.1.1] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Adenylate_cyclase Adenylate cyclase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.1 4.6.1.1] </span> |
|GENE= CYA OR PXO1-122 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1392 Bacillus anthracis]), (CALM1 OR CAM1 OR CALM OR CAM) ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= CYA OR PXO1-122 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1392 Bacillus anthracis]), (CALM1 OR CAM1 OR CALM OR CAM) ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1lvc|1LVC]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1pk0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pk0 OCA], [http://www.ebi.ac.uk/pdbsum/1pk0 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1pk0 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==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. | 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. | ||
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| - | ==Disease== | ||
| - | Known diseases associated with this structure: Cavernous malformations of CNS and retina OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604214 604214]], Cerebral cavernous malformations-1 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604214 604214]], Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604214 604214]], Leukemia, acute T-cell lymphoblastic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603025 603025]], Leukemia, acute myeloid OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603025 603025]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Shen, Y.]] | [[Category: Shen, Y.]] | ||
[[Category: Tang, W J.]] | [[Category: Tang, W J.]] | ||
| - | [[Category: CA]] | ||
| - | [[Category: EMA]] | ||
| - | [[Category: YB]] | ||
[[Category: cam]] | [[Category: cam]] | ||
[[Category: edema factor]] | [[Category: edema factor]] | ||
[[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 Sun Mar 30 23:00:43 2008'' |
Revision as of 20:00, 30 March 2008
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| , resolution 3.30Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , | ||||||
| Gene: | CYA OR PXO1-122 (Bacillus anthracis), (CALM1 OR CAM1 OR CALM OR CAM) (Homo sapiens) | ||||||
| Activity: | Adenylate cyclase, with EC number 4.6.1.1 | ||||||
| Related: | 1LVC
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of the EF3-CaM complexed with PMEApp
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.
About this Structure
1PK0 is a Protein complex structure of sequences from Bacillus anthracis and Homo sapiens. 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
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