1bm7
From Proteopedia
(New page: 200px<br /> <applet load="1bm7" size="450" color="white" frame="true" align="right" spinBox="true" caption="1bm7, resolution 2.00Å" /> '''HUMAN TRANSTHYRETIN...) |
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| - | [[Image:1bm7.gif|left|200px]]<br /> | + | [[Image:1bm7.gif|left|200px]]<br /><applet load="1bm7" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1bm7" size=" | + | |
caption="1bm7, resolution 2.00Å" /> | caption="1bm7, resolution 2.00Å" /> | ||
'''HUMAN TRANSTHYRETIN (PREALBUMIN) COMPLEX WITH FLUFENAMIC ACID (2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID)'''<br /> | '''HUMAN TRANSTHYRETIN (PREALBUMIN) COMPLEX WITH FLUFENAMIC ACID (2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID)'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Insoluble protein fibrils resulting from the self-assembly of a | + | Insoluble protein fibrils resulting from the self-assembly of a conformational intermediate are implicated as the causative agent in several severe human amyloid diseases, including Alzheimer's disease, familial amyloid polyneuropathy, and senile systemic amyloidosis. The latter two diseases are associated with transthyretin (TTR) amyloid fibrils, which appear to form in the acidic partial denaturing environment of the lysosome. Here we demonstrate that flufenamic acid (Flu) inhibits the conformational changes of TTR associated with amyloid fibril formation. The crystal structure of TTR complexed with Flu demonstrates that Flu mediates intersubunit hydrophobic interactions and intersubunit hydrogen bonds that stabilize the normal tetrameric fold of TTR. A small-molecule inhibitor that stabilizes the normal conformation of a protein is desirable as a possible approach to treat amyloid diseases. Molecules such as Flu also provide the means to rigorously test the amyloid hypothesis, i.e., the apparent causative role of amyloid fibrils in amyloid disease. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1BM7 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 FLF as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1BM7 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=FLF:'>FLF</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1BM7 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Kelly, J | + | [[Category: Kelly, J W.]] |
[[Category: Klabunde, T.]] | [[Category: Klabunde, T.]] | ||
| - | [[Category: Sacchettini, J | + | [[Category: Sacchettini, J C.]] |
[[Category: FLF]] | [[Category: FLF]] | ||
[[Category: thyroxine transport]] | [[Category: thyroxine transport]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:56:46 2008'' |
Revision as of 09:56, 21 February 2008
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HUMAN TRANSTHYRETIN (PREALBUMIN) COMPLEX WITH FLUFENAMIC ACID (2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID)
Contents |
Overview
Insoluble protein fibrils resulting from the self-assembly of a conformational intermediate are implicated as the causative agent in several severe human amyloid diseases, including Alzheimer's disease, familial amyloid polyneuropathy, and senile systemic amyloidosis. The latter two diseases are associated with transthyretin (TTR) amyloid fibrils, which appear to form in the acidic partial denaturing environment of the lysosome. Here we demonstrate that flufenamic acid (Flu) inhibits the conformational changes of TTR associated with amyloid fibril formation. The crystal structure of TTR complexed with Flu demonstrates that Flu mediates intersubunit hydrophobic interactions and intersubunit hydrogen bonds that stabilize the normal tetrameric fold of TTR. A small-molecule inhibitor that stabilizes the normal conformation of a protein is desirable as a possible approach to treat amyloid diseases. Molecules such as Flu also provide the means to rigorously test the amyloid hypothesis, i.e., the apparent causative role of amyloid fibrils in amyloid disease.
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
1BM7 is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
Inhibiting transthyretin conformational changes that lead to amyloid fibril formation., Peterson SA, Klabunde T, Lashuel HA, Purkey H, Sacchettini JC, Kelly JW, Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):12956-60. PMID:9789022
Page seeded by OCA on Thu Feb 21 11:56:46 2008
