4HJU
Transthyretin in complex with (E)-N-(3-(4-hydroxy-3,5-dimethylstyryl)phenyl)acrylamide
Summary for 4HJU
Entry DOI | 10.2210/pdb4hju/pdb |
Related | 3CN0 3CN1 3IMR 3IMT 4HJT 4HJU |
Descriptor | Transthyretin, N-{3-[(E)-2-(4-hydroxy-3,5-dimethylphenyl)ethenyl]phenyl}prop-2-enamide (3 entities in total) |
Functional Keywords | hormone binding protein, thyroxine, retinol binding protein, hormone binding protein-inhibitor complex, hormone binding protein/inhibitor |
Biological source | Homo sapiens (human) |
Cellular location | Secreted: P02766 |
Total number of polymer chains | 2 |
Total formula weight | 28141.44 |
Authors | Connelly, S.,Wilson, I.A. (deposition date: 2012-10-14, release date: 2013-12-04, Last modification date: 2023-09-20) |
Primary citation | Suh, E.H.,Liu, Y.,Connelly, S.,Genereux, J.C.,Wilson, I.A.,Kelly, J.W. Stilbene vinyl sulfonamides as fluorogenic sensors of and traceless covalent kinetic stabilizers of transthyretin that prevent amyloidogenesis. J.Am.Chem.Soc., 135:17869-17880, 2013 Cited by PubMed Abstract: Small molecules that react selectively with a specific non-enzyme drug-target protein in a complex biological environment without displacement of a leaving group (tracelessly) are rare and highly desirable. Herein we describe the development of a family of fluorogenic stilbene-based vinyl amides and vinyl sulfonamides that covalently modify transthyretin (TTR) tracelessly. These small molecules bind selectively to TTR in complex biological environments and then undergo a rapid and chemoselective 1,4-Michael addition with the pKa-perturbed Lys-15 ε-amino group of TTR. Replacing the vinyl amide in 2 with the more reactive vinyl sulfonamide in 4 hastens the conjugation kinetics. X-ray cocrystallography verified the formation of the secondary amine bond mediating the conjugation in the case of 2 and 4 and confirmed the expected orientation of the stilbene within the TTR binding sites. Vinyl amide 2 and vinyl sulfonamide 4 potently inhibit TTR dissociation and amyloid fibril formation in vitro. The TTR binding selectivity, modification yield, and reaction chemoselectivity of vinyl sulfonamide 4 are good enough in human plasma to serve as a starting point for medicinal chemistry efforts. Moreover, vinyl sulfonamide 4 is fluorogenic: it exhibits minimal background fluorescence in complex biological environments, remains dark upon binding to TTR, and becomes fluorescent only upon reaction with TTR. The fluorogenicity of 4 was utilized to accurately quantify the native TTR concentration in Escherichia coli lysate using a fluorescence plate reader. PubMed: 24180271DOI: 10.1021/ja408230k PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.35 Å) |
Structure validation
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