2b15
From Proteopedia
(New page: 200px<br /> <applet load="2b15" size="450" color="white" frame="true" align="right" spinBox="true" caption="2b15, resolution 1.7Å" /> '''The crystal structur...) |
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| - | [[Image:2b15.gif|left|200px]]<br /> | + | [[Image:2b15.gif|left|200px]]<br /><applet load="2b15" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2b15" size=" | + | |
caption="2b15, resolution 1.7Å" /> | caption="2b15, resolution 1.7Å" /> | ||
'''The crystal structure of 2,4-dinitrophenol in complex with human transthyretin'''<br /> | '''The crystal structure of 2,4-dinitrophenol in complex with human transthyretin'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Systemic deposition of transthyretin (TTR) amyloid fibrils is always | + | Systemic deposition of transthyretin (TTR) amyloid fibrils is always observed in familial amyloidotic polyneuropathy, senile systemic amyloidosis and familial amyloidotic cardiomyopathy patients. Destabilization of the molecule leads to a cascade of events which result in fibril formation. The destabilization of a native protein with consequent conformational changes appears to be a common link in several human amyloid diseases. Intensive research has been directed towards finding small molecules that could work as therapeutic agents for the prevention/inhibition of amyloid diseases through stabilization of the native fold of the potentially amyloidogenic protein. This work provides insight into the structural determinants of the highly stabilizing effects of 2,4-dinitrophenol on wild-type TTR. It is also shown that similar interactions are established between this molecule and two highly amyloidogenic TTR variants: TTR L55P and TTR Y78F. In the three crystal complexes, 2,4-dinitrophenol occupies the two hormone-binding sites of the TTR tetramer. As a result of 2,4-dinitrophenol binding, the two dimers in the TTR tetramer become closer, increasing the stability of the protein. The three-dimensional structures now determined allow a comprehensive description of key interactions between transthyretin and 2,4-dinitrophenol, a small compound that holds promise as a template for the design of a therapeutical drug for amyloid diseases. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2B15 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 SO4 and DNF as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 2B15 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=SO4:'>SO4</scene> and <scene name='pdbligand=DNF:'>DNF</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2B15 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Damas, A | + | [[Category: Damas, A M.]] |
[[Category: Morais-de-Sa, E.]] | [[Category: Morais-de-Sa, E.]] | ||
| - | [[Category: Neto-Silva, R | + | [[Category: Neto-Silva, R M.]] |
| - | [[Category: Pereira, P | + | [[Category: Pereira, P J.]] |
| - | [[Category: Saraiva, M | + | [[Category: Saraiva, M J.]] |
[[Category: DNF]] | [[Category: DNF]] | ||
[[Category: SO4]] | [[Category: SO4]] | ||
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[[Category: transthyretin]] | [[Category: transthyretin]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:34:37 2008'' |
Revision as of 14:34, 21 February 2008
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The crystal structure of 2,4-dinitrophenol in complex with human transthyretin
Contents |
Overview
Systemic deposition of transthyretin (TTR) amyloid fibrils is always observed in familial amyloidotic polyneuropathy, senile systemic amyloidosis and familial amyloidotic cardiomyopathy patients. Destabilization of the molecule leads to a cascade of events which result in fibril formation. The destabilization of a native protein with consequent conformational changes appears to be a common link in several human amyloid diseases. Intensive research has been directed towards finding small molecules that could work as therapeutic agents for the prevention/inhibition of amyloid diseases through stabilization of the native fold of the potentially amyloidogenic protein. This work provides insight into the structural determinants of the highly stabilizing effects of 2,4-dinitrophenol on wild-type TTR. It is also shown that similar interactions are established between this molecule and two highly amyloidogenic TTR variants: TTR L55P and TTR Y78F. In the three crystal complexes, 2,4-dinitrophenol occupies the two hormone-binding sites of the TTR tetramer. As a result of 2,4-dinitrophenol binding, the two dimers in the TTR tetramer become closer, increasing the stability of the protein. The three-dimensional structures now determined allow a comprehensive description of key interactions between transthyretin and 2,4-dinitrophenol, a small compound that holds promise as a template for the design of a therapeutical drug for amyloid diseases.
Disease
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 Structure
2B15 is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
The binding of 2,4-dinitrophenol to wild-type and amyloidogenic transthyretin., Morais-de-Sa E, Neto-Silva RM, Pereira PJ, Saraiva MJ, Damas AM, Acta Crystallogr D Biol Crystallogr. 2006 May;62(Pt 5):512-9. Epub 2006, Apr 19. PMID:16627944
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