2b77
From Proteopedia
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|PDB= 2b77 |SIZE=350|CAPTION= <scene name='initialview01'>2b77</scene>, resolution 1.70Å | |PDB= 2b77 |SIZE=350|CAPTION= <scene name='initialview01'>2b77</scene>, resolution 1.70Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=3CA:2',4'-DICHLORO-4-HYDROXY-1,1'-BIPHENYL-3-CARBOXYLIC ACID'>3CA</scene> | + | |LIGAND= <scene name='pdbligand=3CA:2',4'-DICHLORO-4-HYDROXY-1,1'-BIPHENYL-3-CARBOXYLIC+ACID'>3CA</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1bm7|1BM7]], [[1dvq|1DVQ]], [[1dvs|1DVS]], [[1dvt|1DVT]], [[1dvx|1DVX]], [[1dvy|1DVY]], [[1bmz|1BMZ]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2b77 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2b77 OCA], [http://www.ebi.ac.uk/pdbsum/2b77 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2b77 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
Analogues of diflunisal, an FDA-approved nonsteroidal antiinflammatory drug (NSAID), were synthesized and evaluated as inhibitors of transthyretin (TTR) aggregation, including amyloid fibril formation. High inhibitory activity was observed for 26 of the compounds. Of those, eight exhibited excellent binding selectivity for TTR in human plasma (binding stoichiometry >0.50, with a theoretical maximum of 2.0 inhibitors bound per TTR tetramer). Biophysical studies reveal that these eight inhibitors dramatically slow tetramer dissociation (the rate-determining step of amyloidogenesis) over a duration of 168 h. This appears to be achieved through ground-state stabilization, which raises the kinetic barrier for tetramer dissociation. Kinetic stabilization of WT TTR by these eight inhibitors is further substantiated by the decreasing rate of amyloid fibril formation as a function of increasing inhibitor concentration (pH 4.4). X-ray cocrystal structures of the TTR.18(2) and TTR.20(2) complexes reveal that 18 and 20 bind in opposite orientations in the TTR binding site. Moving the fluorines from the meta positions in 18 to the ortho positions in 20 reverses the binding orientation, allowing the hydrophilic aromatic ring of 20 to orient in the outer binding pocket where the carboxylate engages in favorable electrostatic interactions with the epsilon-ammonium groups of Lys 15 and 15'. The hydrophilic aryl ring of 18 occupies the inner binding pocket, with the carboxylate positioned to hydrogen bond to the serine 117 and 117' residues. Diflunisal itself appears to occupy both orientations based on the electron density in the TTR.1(2) structure. Structure-activity relationships reveal that para-carboxylate substitution on the hydrophilic ring and dihalogen substitution on the hydrophobic ring afford the most active TTR amyloid inhibitors. | Analogues of diflunisal, an FDA-approved nonsteroidal antiinflammatory drug (NSAID), were synthesized and evaluated as inhibitors of transthyretin (TTR) aggregation, including amyloid fibril formation. High inhibitory activity was observed for 26 of the compounds. Of those, eight exhibited excellent binding selectivity for TTR in human plasma (binding stoichiometry >0.50, with a theoretical maximum of 2.0 inhibitors bound per TTR tetramer). Biophysical studies reveal that these eight inhibitors dramatically slow tetramer dissociation (the rate-determining step of amyloidogenesis) over a duration of 168 h. This appears to be achieved through ground-state stabilization, which raises the kinetic barrier for tetramer dissociation. Kinetic stabilization of WT TTR by these eight inhibitors is further substantiated by the decreasing rate of amyloid fibril formation as a function of increasing inhibitor concentration (pH 4.4). X-ray cocrystal structures of the TTR.18(2) and TTR.20(2) complexes reveal that 18 and 20 bind in opposite orientations in the TTR binding site. Moving the fluorines from the meta positions in 18 to the ortho positions in 20 reverses the binding orientation, allowing the hydrophilic aromatic ring of 20 to orient in the outer binding pocket where the carboxylate engages in favorable electrostatic interactions with the epsilon-ammonium groups of Lys 15 and 15'. The hydrophilic aryl ring of 18 occupies the inner binding pocket, with the carboxylate positioned to hydrogen bond to the serine 117 and 117' residues. Diflunisal itself appears to occupy both orientations based on the electron density in the TTR.1(2) structure. Structure-activity relationships reveal that para-carboxylate substitution on the hydrophilic ring and dihalogen substitution on the hydrophobic ring afford the most active TTR amyloid inhibitors. | ||
| - | |||
| - | ==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: Palaninathan, S K.]] | [[Category: Palaninathan, S K.]] | ||
[[Category: Sacchettini, J C.]] | [[Category: Sacchettini, J C.]] | ||
| - | [[Category: 3CA]] | ||
[[Category: amyloid]] | [[Category: amyloid]] | ||
[[Category: transthyretin]] | [[Category: transthyretin]] | ||
[[Category: ttr]] | [[Category: ttr]] | ||
| - | ''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 02:02:22 2008'' |
Revision as of 23:02, 30 March 2008
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| , resolution 1.70Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Related: | 1BM7, 1DVQ, 1DVS, 1DVT, 1DVX, 1DVY, 1BMZ
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Human transthyretin (TTR) complexed with Diflunisal analogues- TTR.2',4'-DICHLORO-4-HYDROXY-1,1'-BIPHENYL-3-CARBOXYLIC ACID
Overview
Analogues of diflunisal, an FDA-approved nonsteroidal antiinflammatory drug (NSAID), were synthesized and evaluated as inhibitors of transthyretin (TTR) aggregation, including amyloid fibril formation. High inhibitory activity was observed for 26 of the compounds. Of those, eight exhibited excellent binding selectivity for TTR in human plasma (binding stoichiometry >0.50, with a theoretical maximum of 2.0 inhibitors bound per TTR tetramer). Biophysical studies reveal that these eight inhibitors dramatically slow tetramer dissociation (the rate-determining step of amyloidogenesis) over a duration of 168 h. This appears to be achieved through ground-state stabilization, which raises the kinetic barrier for tetramer dissociation. Kinetic stabilization of WT TTR by these eight inhibitors is further substantiated by the decreasing rate of amyloid fibril formation as a function of increasing inhibitor concentration (pH 4.4). X-ray cocrystal structures of the TTR.18(2) and TTR.20(2) complexes reveal that 18 and 20 bind in opposite orientations in the TTR binding site. Moving the fluorines from the meta positions in 18 to the ortho positions in 20 reverses the binding orientation, allowing the hydrophilic aromatic ring of 20 to orient in the outer binding pocket where the carboxylate engages in favorable electrostatic interactions with the epsilon-ammonium groups of Lys 15 and 15'. The hydrophilic aryl ring of 18 occupies the inner binding pocket, with the carboxylate positioned to hydrogen bond to the serine 117 and 117' residues. Diflunisal itself appears to occupy both orientations based on the electron density in the TTR.1(2) structure. Structure-activity relationships reveal that para-carboxylate substitution on the hydrophilic ring and dihalogen substitution on the hydrophobic ring afford the most active TTR amyloid inhibitors.
About this Structure
2B77 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis., Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW, J Med Chem. 2004 Jan 15;47(2):355-74. PMID:14711308
Page seeded by OCA on Mon Mar 31 02:02:22 2008
