1thc: Difference between revisions
New page: left|200px<br /> <applet load="1thc" size="450" color="white" frame="true" align="right" spinBox="true" caption="1thc, resolution 2.3Å" /> '''CRYSTAL STRUCTURE DE... |
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[[Image:1thc.gif|left|200px]]<br /> | [[Image:1thc.gif|left|200px]]<br /><applet load="1thc" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1thc, resolution 2.3Å" /> | caption="1thc, resolution 2.3Å" /> | ||
'''CRYSTAL STRUCTURE DETERMINATION AT 2.3A OF HUMAN TRANSTHYRETIN-3',5'-DIBROMO-2',4,4',6-TETRA-HYDROXYAURONE COMPLEX'''<br /> | '''CRYSTAL STRUCTURE DETERMINATION AT 2.3A OF HUMAN TRANSTHYRETIN-3',5'-DIBROMO-2',4,4',6-TETRA-HYDROXYAURONE COMPLEX'''<br /> | ||
==Overview== | ==Overview== | ||
The crystal structure of the complex of | The crystal structure of the complex of 3',5'-dibromo-2',4,4',6-tetrahydroxyaurone, a flavone derivative, with human transthyretin (TTR), a serum thyroid hormone transport protein, has been determined and refined to R = 17.9% for data to 2.3-A resolution and provides a detailed description of a protein-bound flavonoid structure. This bromoaurone is a potent competitor for thyroid hormone binding to TTR, a 54,980-dalton alpha 4 tetrameric protein of 222 molecular symmetry, as well as an inhibitor of iodothyronine deiodinase. Crystals of the TTR-bromoaurone complex are isomorphous to those of native TTR. Interpretation of difference Fourier electron density maps revealed two binding modes for the bromoaurone in each of the two independent binding sites of the TTR tetramer: deep in the channel near Ser-117 (mode I) and near the channel entrance (mode II). None of the binding modes can be fully occupied because of overlap between binding positions. A statistical disorder for bromoaurone binding was also applied, as it binds along the twofold crystallographic axis and does not possess such symmetry. The binding of mode I and that of mode II were refined at half occupancy, resulting in two molecules per tetramer. The bromoaurone binds in a nonplanar antiskewed conformation. The molecular pattern for TTR binding consists of halogen groups able to anchor between beta-sheets to form both hydrophobic and hydrophilic contacts. Comparison of structural data for bromoaurone- and thyroxine-TTR complexes indicates that bromoaurone binding mode I is 3 A deeper in the channel and binding mode II is 4 A further from the channel center than thyroxine. The bromoaurone binding observed in this TTR complex differs significantly from that based upon computer modeling studies. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1THC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with FL9 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | 1THC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=FL9:'>FL9</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1THC OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Ciszak, E.]] | [[Category: Ciszak, E.]] | ||
[[Category: Cody, V.]] | [[Category: Cody, V.]] | ||
[[Category: Luft, J | [[Category: Luft, J R.]] | ||
[[Category: FL9]] | [[Category: FL9]] | ||
[[Category: retinol) in serum]] | [[Category: retinol) in serum]] | ||
[[Category: transport (thyroxine]] | [[Category: transport (thyroxine]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:13:29 2008'' | ||
Revision as of 16:13, 21 February 2008
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CRYSTAL STRUCTURE DETERMINATION AT 2.3A OF HUMAN TRANSTHYRETIN-3',5'-DIBROMO-2',4,4',6-TETRA-HYDROXYAURONE COMPLEX
OverviewOverview
The crystal structure of the complex of 3',5'-dibromo-2',4,4',6-tetrahydroxyaurone, a flavone derivative, with human transthyretin (TTR), a serum thyroid hormone transport protein, has been determined and refined to R = 17.9% for data to 2.3-A resolution and provides a detailed description of a protein-bound flavonoid structure. This bromoaurone is a potent competitor for thyroid hormone binding to TTR, a 54,980-dalton alpha 4 tetrameric protein of 222 molecular symmetry, as well as an inhibitor of iodothyronine deiodinase. Crystals of the TTR-bromoaurone complex are isomorphous to those of native TTR. Interpretation of difference Fourier electron density maps revealed two binding modes for the bromoaurone in each of the two independent binding sites of the TTR tetramer: deep in the channel near Ser-117 (mode I) and near the channel entrance (mode II). None of the binding modes can be fully occupied because of overlap between binding positions. A statistical disorder for bromoaurone binding was also applied, as it binds along the twofold crystallographic axis and does not possess such symmetry. The binding of mode I and that of mode II were refined at half occupancy, resulting in two molecules per tetramer. The bromoaurone binds in a nonplanar antiskewed conformation. The molecular pattern for TTR binding consists of halogen groups able to anchor between beta-sheets to form both hydrophobic and hydrophilic contacts. Comparison of structural data for bromoaurone- and thyroxine-TTR complexes indicates that bromoaurone binding mode I is 3 A deeper in the channel and binding mode II is 4 A further from the channel center than thyroxine. The bromoaurone binding observed in this TTR complex differs significantly from that based upon computer modeling studies.
DiseaseDisease
Known diseases associated with this structure: Amyloid neuropathy, familial, several allelic types OMIM:[176300], Amyloidosis, senile systemic OMIM:[176300], Carpal tunnel syndrome, familial OMIM:[176300], Dystransthyretinemic hyperthyroxinemia OMIM:[176300]
About this StructureAbout this Structure
1THC is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure determination at 2.3-A resolution of human transthyretin-3',5'-dibromo-2',4,4',6-tetrahydroxyaurone complex., Ciszak E, Cody V, Luft JR, Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6644-8. PMID:1631168
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