1sk6
From Proteopedia
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|PDB= 1sk6 |SIZE=350|CAPTION= <scene name='initialview01'>1sk6</scene>, resolution 3.2Å | |PDB= 1sk6 |SIZE=350|CAPTION= <scene name='initialview01'>1sk6</scene>, resolution 3.2Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA | + | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CMP:ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE'>CMP</scene>, <scene name='pdbligand=POP:PYROPHOSPHATE+2-'>POP</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, PXO1-122 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1392 Bacillus anthracis]) | |GENE= CYA, PXO1-122 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1392 Bacillus anthracis]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1k90|1k90]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1sk6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1sk6 OCA], [http://www.ebi.ac.uk/pdbsum/1sk6 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1sk6 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==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. | 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. | ||
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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: Tang, W J.]] | [[Category: Tang, W J.]] | ||
[[Category: Zhukovskaya, N L.]] | [[Category: Zhukovskaya, N L.]] | ||
| - | [[Category: CA]] | ||
| - | [[Category: CMP]] | ||
| - | [[Category: POP]] | ||
| - | [[Category: YB]] | ||
[[Category: ef3 camp ppi cam]] | [[Category: ef3 camp ppi cam]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 23 | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:43:08 2008'' |
Revision as of 20:43, 30 March 2008
| |||||||
| , resolution 3.2Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , , | ||||||
| Gene: | CYA, PXO1-122 (Bacillus anthracis) | ||||||
| Activity: | Adenylate cyclase, with EC number 4.6.1.1 | ||||||
| Related: | 1k90
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of the adenylyl cyclase domain of anthrax edema factor (EF) in complex with calmodulin, 3',5' cyclic AMP (cAMP), and pyrophosphate
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.
About this Structure
1SK6 is a Protein complex structure of sequences from Bacillus anthracis and Homo sapiens. 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
Page seeded by OCA on Sun Mar 30 23:43:08 2008
