1y1d
From Proteopedia
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|PDB= 1y1d |SIZE=350|CAPTION= <scene name='initialview01'>1y1d</scene>, resolution 1.70Å | |PDB= 1y1d |SIZE=350|CAPTION= <scene name='initialview01'>1y1d</scene>, resolution 1.70Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=FHI:2',4'-DIFLUORO-4-HYDROXY-5-IODO-1,1'-BIPHENYL-3-CARBOXYLIC ACID'>FHI</scene> | + | |LIGAND= <scene name='pdbligand=FHI:2',4'-DIFLUORO-4-HYDROXY-5-IODO-1,1'-BIPHENYL-3-CARBOXYLIC+ACID'>FHI</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= TTR, PALB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= TTR, PALB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1y1d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1y1d OCA], [http://www.ebi.ac.uk/pdbsum/1y1d PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1y1d RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==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. | 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:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176300 176300]], Amyloidosis, senile systemic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176300 176300]], Carpal tunnel syndrome, familial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176300 176300]], Dystransthyretinemic hyperthyroxinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176300 176300]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Saraiva, M J.]] | [[Category: Saraiva, M J.]] | ||
[[Category: Valencia, G.]] | [[Category: Valencia, G.]] | ||
| - | [[Category: FHI]] | ||
[[Category: amyloid]] | [[Category: amyloid]] | ||
[[Category: iododiflunisal]] | [[Category: iododiflunisal]] | ||
[[Category: transthyretin]] | [[Category: transthyretin]] | ||
| - | ''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 00:57:31 2008'' |
Revision as of 21:57, 30 March 2008
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| , resolution 1.70Å | |||||||
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| Ligands: | |||||||
| Gene: | TTR, PALB (Homo sapiens) | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of transthyretin in complex with iododiflunisal
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.
About this Structure
1Y1D is a Single protein structure of sequence from Homo sapiens. 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
Page seeded by OCA on Mon Mar 31 00:57:31 2008
