4I87

Crystal structure of TTR variant I84S in complex with CHF5074 at acidic pH

Summary for 4I87

• Entry DOI: 10.2210/pdb4i87/pdb
• Related: 4I85 4I89
• Descriptor: Transthyretin, 1-(3',4'-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid (3 entities in total)
• Functional Keywords: transthyretin, amyloidosis, fibrillogenesis inhibitors, protein misfolding, t3 or t4 hormone, plasma, transport protein-inhibitor complex, transport protein/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 28152.88

Authors

Zanotti, G.,Cendron, L.,Folli, C.,Florio, P.,Imbimbo, B.P.,Berni, R. (deposition date: 2012-12-03, release date: 2013-06-19, Last modification date: 2023-09-20)

Primary citation

Zanotti, G.,Cendron, L.,Folli, C.,Florio, P.,Imbimbo, B.P.,Berni, R.
Structural evidence for native state stabilization of a conformationally labile amyloidogenic transthyretin variant by fibrillogenesis inhibitors.
Febs Lett., 587:2325-2331, 2013

PubMed Abstract: Several classes of chemicals are able to bind to the thyroxine binding sites of transthyretin (TTR), stabilizing its native state and inhibiting in vitro the amyloidogenic process. The amyloidogenic I84S TTR variant undergoes a large conformational change at moderately acidic pH. Structural evidence has been obtained by X-ray analysis for the native state stabilization of I84S TTR by two chemically distinct fibrillogenesis inhibitors. In fact, they fully prevent the acidic pH-induced protein conformational change as a result of a long-range stabilizing effect. This study provides further support to the therapeutic strategy based on the use of TTR stabilizers as anti-amyloidogenic drugs.

PubMed: 23792159
DOI: 10.1016/j.febslet.2013.06.016

Experimental method

X-RAY DIFFRACTION (1.69 Å)