3HJ0

Transthyretin in complex with a covalent small molecule kinetic stabilizer

Summary for 3HJ0

• Entry DOI: 10.2210/pdb3hj0/pdb
• Related: 3CN1 3CN2 3CN3 3CN4
• Descriptor: Transthyretin, 4-fluorophenyl 3-[(E)-2-(4-hydroxy-3,5-dimethylphenyl)ethenyl]benzoate (3 entities in total)
• Functional Keywords: hormone, growth factor, amyloid, disease mutation, gamma-carboxyglutamic acid, glycoprotein, polyneuropathy, retinol-binding, secreted, thyroid hormone, transport, vitamin a
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 28343.51

Authors

Connelly, S.,Wilson, I.A.,Kelly, J.W. (deposition date: 2009-05-20, release date: 2009-12-22, Last modification date: 2014-11-19)

Primary citation

Choi, S.,Connelly, S.,Reixach, N.,Wilson, I.A.,Kelly, J.W.
Chemoselective small molecules that covalently modify one lysine in a non-enzyme protein in plasma.
Nat.Chem.Biol., 6:133-139, 2010

PubMed Abstract: A small molecule that could bind selectively to and then react chemoselectively with a non-enzyme protein in a complex biological fluid, such as blood, could have numerous practical applications. Herein, we report a family of designed stilbenes that selectively and covalently modify the prominent plasma protein transthyretin in preference to more than 4,000 other human plasma proteins. They react chemoselectively with only one of eight lysine e-amino groups within transthyretin. The crystal structure confirms the expected binding orientation of the stilbene substructure and the anticipated conjugating amide bond. These covalent transthyretin kinetic stabilizers exhibit superior amyloid inhibition potency compared to their noncovalent counterparts, and they prevent cytotoxicity associated with amyloidogenesis. Though there are a few prodrugs that, upon metabolic activation, react with a cysteine residue inactivating a specific non-enzyme, we are unaware of designed small molecules that react with one lysine e-amine within a specific non-enzyme protein in a complex biological fluid.

PubMed: 20081815
DOI: 10.1038/nchembio.281

Experimental method

X-RAY DIFFRACTION (1.34 Å)