1BMZ

HUMAN TRANSTHYRETIN (PREALBUMIN)

Summary for 1BMZ

• Entry DOI: 10.2210/pdb1bmz/pdb
• Descriptor: PROTEIN (TRANSTHYRETIN) (2 entities in total)
• Functional Keywords: thyroxine transport, hormone-growth factor complex, hormone/growth factor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 27554.72

Authors

Klabunde, T.,Kelly, J.W.,Sacchettini, J.C. (deposition date: 1998-07-27, release date: 1998-08-05, Last modification date: 2024-02-07)

Primary citation

Peterson, S.A.,Klabunde, T.,Lashuel, H.A.,Purkey, H.,Sacchettini, J.C.,Kelly, J.W.
Inhibiting transthyretin conformational changes that lead to amyloid fibril formation.
Proc.Natl.Acad.Sci.USA, 95:12956-12960, 1998

PubMed Abstract: 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.

PubMed: 9789022
DOI: 10.1073/pnas.95.22.12956

Experimental method

X-RAY DIFFRACTION (2 Å)