Binding of Monovalent
and Bivalent Ligands by Transthyretin
Causes Different Short- and Long-Distance Conformational Changes
Posted on 2019-08-22 - 19:40
The wild type protein,
transthyretin (TTR), and over 120 genetic
TTR variants are amyloidogenic and cause, respectively, sporadic and
hereditary systemic TTR amyloidosis. The homotetrameric TTR contains
two identical thyroxine binding pockets, occupation of which by specific
ligands can inhibit TTR amyloidogenesis in vitro. Ligand binding stabilizes
the tetramer, inhibiting its proteolytic cleavage and its dissociation.
Here, we show with solution-state NMR that ligand binding induces
long-distance conformational changes in the TTR that have not previously
been detected by X-ray crystallography, consistently with the inhibition
of the cleavage of the DE loop. The NMR findings, coupled with surface
plasmon resonance measurements, have identified dynamic exchange processes
underlying the negative cooperativity of binding of “monovalent”
ligand tafamidis. In contrast, mds84, our prototypic “bivalent”
ligand, which is a more potent stabilizer of TTR in vitro that occupies
both thyroxine pockets and the intramolecular channel between them,
has greater structural effects.
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Corazza, Alessandra; Verona, Guglielmo; Waudby, Christopher A.; Mangione, P. Patrizia; Bingham, Ryan; Uings, Iain; et al. (2019). Binding of Monovalent
and Bivalent Ligands by Transthyretin
Causes Different Short- and Long-Distance Conformational Changes. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.9b01037
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AUTHORS (12)
AC
Alessandra Corazza
GV
Guglielmo Verona
CW
Christopher A. Waudby
PM
P. Patrizia Mangione
RB
Ryan Bingham
IU
Iain Uings
DC
Diana Canetti
PN
Paola Nocerino
GT
Graham W. Taylor
MP
Mark B. Pepys
JC
John Christodoulou
VB
Vittorio Bellotti
KEYWORDS
TTR amyloidogenesisLigand bindingBivalent Ligandsexchange processesTTR amyloidosisNMR findingsligand bindingTransthyretin Causeshomotetrameric TTRLong-Distance Conformational Changesthyroxine pocketsX-ray crystallographysurface plasmon resonance measurementsDE looptype proteinsolution-state NMRTTR variantsintramolecular channelthyroxine binding pockets