1y1d
From Proteopedia
(New page: 200px<br /> <applet load="1y1d" size="450" color="white" frame="true" align="right" spinBox="true" caption="1y1d, resolution 1.70Å" /> '''Crystal structure o...) |
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| - | [[Image:1y1d.gif|left|200px]]<br /> | + | [[Image:1y1d.gif|left|200px]]<br /><applet load="1y1d" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1y1d" size=" | + | |
caption="1y1d, resolution 1.70Å" /> | caption="1y1d, resolution 1.70Å" /> | ||
'''Crystal structure of transthyretin in complex with iododiflunisal'''<br /> | '''Crystal structure of transthyretin in complex with iododiflunisal'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Ex vivo and in vitro studies have revealed the remarkable amyloid | + | Ex vivo and in vitro studies have revealed the remarkable amyloid inhibitory potency and specificity of iododiflunisal in relation to transthyretin [Almeida, Macedo, Cardoso, Alves, Valencia, Arsequell, Planas and Saraiva (2004) Biochem. J. 381, 351-356], a protein implicated in familial amyloidotic polyneuropathy. In the present paper, the crystal structure of transthyretin complexed with this diflunisal derivative is reported, which enables a detailed analysis of the protein-ligand interactions. Iododiflunisal binds very deep in the hormone-binding channel. The iodine substituent is tightly anchored into a pocket of the binding site and the fluorine atoms provide extra hydrophobic contacts with the protein. The carboxylate substituent is involved in an electrostatic interaction with the N(zeta) of a lysine residue. Moreover, ligand-induced conformational alterations in the side chain of some residues result in the formation of new intersubunit hydrogen bonds. All these new interactions, induced by iododiflunisal, increase the stability of the tetramer impairing the formation of amyloid fibrils. The crystal structure of this complex opens perspectives for the design of more specific and effective drugs for familial amyloidotic polyneuropathy patients. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1Y1D 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 FHI as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1Y1D 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=FHI:'>FHI</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Y1D OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Arsequell, G.]] | [[Category: Arsequell, G.]] | ||
| - | [[Category: Damas, A | + | [[Category: Damas, A M.]] |
[[Category: Gales, L.]] | [[Category: Gales, L.]] | ||
[[Category: Macedo-Ribeiro, S.]] | [[Category: Macedo-Ribeiro, S.]] | ||
| - | [[Category: Saraiva, M | + | [[Category: Saraiva, M J.]] |
[[Category: Valencia, G.]] | [[Category: Valencia, G.]] | ||
[[Category: FHI]] | [[Category: FHI]] | ||
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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 16:00:49 2008'' |
Revision as of 14:00, 21 February 2008
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Crystal structure of transthyretin in complex with iododiflunisal
Contents |
Overview
Ex vivo and in vitro studies have revealed the remarkable amyloid inhibitory potency and specificity of iododiflunisal in relation to transthyretin [Almeida, Macedo, Cardoso, Alves, Valencia, Arsequell, Planas and Saraiva (2004) Biochem. J. 381, 351-356], a protein implicated in familial amyloidotic polyneuropathy. In the present paper, the crystal structure of transthyretin complexed with this diflunisal derivative is reported, which enables a detailed analysis of the protein-ligand interactions. Iododiflunisal binds very deep in the hormone-binding channel. The iodine substituent is tightly anchored into a pocket of the binding site and the fluorine atoms provide extra hydrophobic contacts with the protein. The carboxylate substituent is involved in an electrostatic interaction with the N(zeta) of a lysine residue. Moreover, ligand-induced conformational alterations in the side chain of some residues result in the formation of new intersubunit hydrogen bonds. All these new interactions, induced by iododiflunisal, increase the stability of the tetramer impairing the formation of amyloid fibrils. The crystal structure of this complex opens perspectives for the design of more specific and effective drugs for familial amyloidotic polyneuropathy patients.
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
1Y1D is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
Human transthyretin in complex with iododiflunisal: structural features associated with a potent amyloid inhibitor., Gales L, Macedo-Ribeiro S, Arsequell G, Valencia G, Saraiva MJ, Damas AM, Biochem J. 2005 Jun 1;388(Pt 2):615-21. PMID:15689188
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