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 Cited by 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: 20081815DOI: 10.1038/nchembio.281 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.34 Å) |
Structure validation
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