2a3x
From Proteopedia
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|PDB= 2a3x |SIZE=350|CAPTION= <scene name='initialview01'>2a3x</scene>, resolution 3.00Å | |PDB= 2a3x |SIZE=350|CAPTION= <scene name='initialview01'>2a3x</scene>, resolution 3.00Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene> | + | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CPK:BIS-1,2-{[(Z)-2CARBOXY-2-METHYL-1,3-DIOXANE]-5-YLOXYCARBONYL}-PIPERAZINE'>CPK</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1lgn|1LGN]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2a3x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a3x OCA], [http://www.ebi.ac.uk/pdbsum/2a3x PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2a3x RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
A comprehensive series of solution and crystallographic studies reveal how simple, achiral, bivalent ligands of the cyclic pyruvate of glycerol promote face-to-face complex formation of the pentraxin, serum amyloid P component (SAP) into decamers. SAP, a protein of the human innate immune system, is universally present in amyloids, including cerebral amyloid deposits found in the brain of Alzheimer disease patients. Removal of SAP through a specific aggregation mechanism mediated by multivalent ligands appears to provide therapeutic benefit in the progression of this disease. Crystallographic studies reveal that in our novel series of ligands only the methyl and carboxylate moieties of the pyruvate ketal directly interact with the protein, but the geometric constraints imposed by the tether dictate which of two chair conformations are adopted by the pyruvate dioxane ring. Solution studies, as interpreted through a simple thermodynamic model, account for the distribution of pentameric and decameric bound states at different ligand concentrations and indicate that differences in the flexibility of the tether determine the geometry and stability of the specific aggregates formed between SAP and two different bivalent ligands. The factors affecting the design of ligands promoting face-to-face protein dimerization as well as potential biological implications are discussed. | A comprehensive series of solution and crystallographic studies reveal how simple, achiral, bivalent ligands of the cyclic pyruvate of glycerol promote face-to-face complex formation of the pentraxin, serum amyloid P component (SAP) into decamers. SAP, a protein of the human innate immune system, is universally present in amyloids, including cerebral amyloid deposits found in the brain of Alzheimer disease patients. Removal of SAP through a specific aggregation mechanism mediated by multivalent ligands appears to provide therapeutic benefit in the progression of this disease. Crystallographic studies reveal that in our novel series of ligands only the methyl and carboxylate moieties of the pyruvate ketal directly interact with the protein, but the geometric constraints imposed by the tether dictate which of two chair conformations are adopted by the pyruvate dioxane ring. Solution studies, as interpreted through a simple thermodynamic model, account for the distribution of pentameric and decameric bound states at different ligand concentrations and indicate that differences in the flexibility of the tether determine the geometry and stability of the specific aggregates formed between SAP and two different bivalent ligands. The factors affecting the design of ligands promoting face-to-face protein dimerization as well as potential biological implications are discussed. | ||
| - | |||
| - | ==Disease== | ||
| - | Known disease associated with this structure: Amyloidosis, secondary, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=104770 104770]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Paszkiewicz, E.]] | [[Category: Paszkiewicz, E.]] | ||
[[Category: Sadowska, J.]] | [[Category: Sadowska, J.]] | ||
| - | [[Category: CA]] | ||
| - | [[Category: CPK]] | ||
[[Category: multivalent ligand]] | [[Category: multivalent ligand]] | ||
[[Category: serum amyloid]] | [[Category: serum amyloid]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:47:35 2008'' |
Revision as of 22:47, 30 March 2008
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| , resolution 3.00Å | |||||||
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| Ligands: | , | ||||||
| Related: | 1LGN
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Decameric crystal structure of human serum amyloid P-component bound to Bis-1,2-{[(Z)-2carboxy- 2-methyl-1,3-dioxane]- 5-yloxycarbonyl}-piperazine
Overview
A comprehensive series of solution and crystallographic studies reveal how simple, achiral, bivalent ligands of the cyclic pyruvate of glycerol promote face-to-face complex formation of the pentraxin, serum amyloid P component (SAP) into decamers. SAP, a protein of the human innate immune system, is universally present in amyloids, including cerebral amyloid deposits found in the brain of Alzheimer disease patients. Removal of SAP through a specific aggregation mechanism mediated by multivalent ligands appears to provide therapeutic benefit in the progression of this disease. Crystallographic studies reveal that in our novel series of ligands only the methyl and carboxylate moieties of the pyruvate ketal directly interact with the protein, but the geometric constraints imposed by the tether dictate which of two chair conformations are adopted by the pyruvate dioxane ring. Solution studies, as interpreted through a simple thermodynamic model, account for the distribution of pentameric and decameric bound states at different ligand concentrations and indicate that differences in the flexibility of the tether determine the geometry and stability of the specific aggregates formed between SAP and two different bivalent ligands. The factors affecting the design of ligands promoting face-to-face protein dimerization as well as potential biological implications are discussed.
About this Structure
2A3X is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Ligand-assisted aggregation of proteins. Dimerization of serum amyloid P component by bivalent ligands., Ho JG, Kitov PI, Paszkiewicz E, Sadowska J, Bundle DR, Ng KK, J Biol Chem. 2005 Sep 9;280(36):31999-2008. Epub 2005 Jul 20. PMID:16036920
Page seeded by OCA on Mon Mar 31 01:47:35 2008
