1sk6

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spinqualitylabelsall models 1sk6, resolution 3.2Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of the adenylyl cyclase domain of anthrax edema factor (EF) in complex with calmodulin, 3',5' cyclic AMP (cAMP), and pyrophosphate

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Anthrax edema factor (EF) raises host intracellular cAMP to pathological, levels through a calcium-calmodulin (CaM)-dependent adenylyl cyclase, activity. Here we report the structure of EF.CaM in complex with its, reaction products, cAMP and PP(i). Mutational analysis confirmed the, interaction of EF with cAMP and PP(i) as depicted in the structural model., While both cAMP and PP(i) have access to solvent channels to exit, independently, PP(i) is likely released first. EF can synthesize ATP from, cAMP and PP(i), and the estimated rate constants of this reaction at two, physiologically relevant calcium concentrations were similar to those of, adenylyl cyclase activity of EF. Comparison of the conformation of, adenosine in the structures of EF.CaM.cAMP.PP(i) with EF.CaM.3.dATP, revealed about 160 degrees rotation in the torsion angle of N-glycosyl, bond from the +anti conformation in 3.dATP to -syn in cAMP; such a, rotation could serve to distinguish against substrates with the N-2 amino, group of purine. The catalytic rate of EF for ITP was about 2 orders of, magnitude better than that for GTP, supporting the potential role of this, rotation in substrate selectivity of EF. The anomalous difference Fourier, map revealed that two ytterbium ions (Yb(3+)) could bind the catalytic, site of EF.CaM in the presence of cAMP and PP(i), suggesting the presence, of two magnesium ions at the catalytic site of EF. We hypothesize that EF, could use a "histidine and two-metal ion" hybrid mechanism to facilitate, the cyclization reaction.

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

1SK6 is a Protein complex structure of sequences from Bacillus anthracis and Homo sapiens with CA, YB, CMP and POP as ligands. Active as Adenylate cyclase, with EC number 4.6.1.1 Full crystallographic information is available from OCA.

Reference

Structural and kinetic analyses of the interaction of anthrax adenylyl cyclase toxin with reaction products cAMP and pyrophosphate., Guo Q, Shen Y, Zhukovskaya NL, Florian J, Tang WJ, J Biol Chem. 2004 Jul 9;279(28):29427-35. Epub 2004 May 6. PMID:15131111

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