1bm7: Difference between revisions
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|PDB= 1bm7 |SIZE=350|CAPTION= <scene name='initialview01'>1bm7</scene>, resolution 2.00Å | |PDB= 1bm7 |SIZE=350|CAPTION= <scene name='initialview01'>1bm7</scene>, resolution 2.00Å | ||
|SITE= | |SITE= | ||
|LIGAND= <scene name='pdbligand=FLF:2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID'>FLF</scene> | |LIGAND= <scene name='pdbligand=FLF:2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO]+BENZOIC+ACID'>FLF</scene> | ||
|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
|DOMAIN= | |||
|RELATEDENTRY= | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1bm7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1bm7 OCA], [http://www.ebi.ac.uk/pdbsum/1bm7 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1bm7 RCSB]</span> | |||
}} | }} | ||
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==Overview== | ==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. | 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. | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Klabunde, T.]] | [[Category: Klabunde, T.]] | ||
[[Category: Sacchettini, J C.]] | [[Category: Sacchettini, J C.]] | ||
[[Category: thyroxine transport]] | [[Category: thyroxine transport]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 19:03:54 2008'' | ||
