1PK0

Crystal Structure of the EF3-CaM complexed with PMEApp

Summary for 1PK0

• Entry DOI: 10.2210/pdb1pk0/pdb
• Related: 1LVC
• Descriptor: Calmodulin-sensitive adenylate cyclase, Calmodulin, YTTERBIUM (III) ION, ... (6 entities in total)
• Functional Keywords: edema factor, cam, prodrug complex, lyase-metal binding protein complex, lyase/metal binding protein
• Biological source: Bacillus anthracis; More
• Total number of polymer chains: 6
• Total formula weight: 227147.18

Authors

Shen, Y.,Tang, W.J. (deposition date: 2003-06-04, release date: 2004-02-10, Last modification date: 2024-04-03)

Primary citation

Shen, Y.,Zhukovskaya, N.L.,Zimmer, M.I.,Soelaiman, S.,Bergson, P.,Wang, C.R.,Gibbs, C.S.,Tang, W.J.
Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection.
Proc.Natl.Acad.Sci.USA, 101:3242-3247, 2004

PubMed Abstract: 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.

PubMed: 14978283
DOI: 10.1073/pnas.0306552101

Experimental method

X-RAY DIFFRACTION (3.3 Å)