6R68

Crystal structure of transthyretin in complex with CHF4795, a flurbiprofen analogue

Summary for 6R68

• Entry DOI: 10.2210/pdb6r68/pdb
• Descriptor: Transthyretin, (2~{R})-2-[4-[3,5-bis(chloranyl)phenyl]-3-fluoranyl-phenyl]propanoic acid (3 entities in total)
• Functional Keywords: amyloidosis, tetramer, binding protein, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 32436.27

Authors

Loconte, V.,Menozzi, I.,Ferrari, A.,Berni, R.,Zanotti, G. (deposition date: 2019-03-26, release date: 2019-09-11, Last modification date: 2024-05-15)

Primary citation

Loconte, V.,Menozzi, I.,Ferrari, A.,Folli, C.,Imbimbo, B.P.,Zanotti, G.,Berni, R.
Structure-activity relationships of flurbiprofen analogues as stabilizers of the amyloidogenic protein transthyretin.
J.Struct.Biol., 208:165-173, 2019

PubMed Abstract: The inherent amyloidogenic potentialof wild type transthyretin (TTR) is enhanced by a large number of point mutations, which destabilize the TTR tetramer, thereby promoting its disassembly and pathological aggregation responsible for TTR-related amyloidosis. TTR stabilizers are able to interact with the thyroxine-binding sites of TTR, stabilizing its tetrameric native state and inhibiting amyloidogenesis. Herein, we report on in vitro, ex vivo, and X-ray analyses to assess the TTR structural stabilization by analogues of flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID). Overall, considering together binding selectivity and protective effects on TTR native structure by flurbiprofen analogues in the presence of plasma proteins, as determined by Western Blot,the aforementioned properties of analyzed compounds appear to be better (CHF5075 and CHF4802) or similar (CHF4795) or worse (CHF5074, also known as CSP-1103) as compared to those of diflunisal, used as a reference TTR stabilizer. Molecular details of the determinants affecting the interactionsof CHF5075, CHF4802, and CHF4795 with wild type TTRand of CHF5074 withtheamyloidogenic A25TTTR variant havebeen elucidated by X-ray analysis. Distinct interactions with TTR appear to characterize flurbiprofen analogues and the NSAID diflunisal and its analogues as TTR stabilizers. Relationships between stabilizing effect on TTR by flurbiprofen analogues determined experimentally and molecular details of their interactions with TTR have been established, providing the rationale for their protective effects on the native protein structure.

PubMed: 31473362
DOI: 10.1016/j.jsb.2019.08.011

Experimental method

X-RAY DIFFRACTION (1.45 Å)