Details
| Original language | English |
|---|---|
| Pages (from-to) | 6628–6635 |
| Number of pages | 8 |
| Journal | The Journal of Physical Chemistry Part B: Biophysics, Biomaterials, Liquids, Soft Matter |
| Volume | 127 |
| Issue number | 30 |
| Early online date | 21 Jul 2023 |
| Publication status | Published - 3 Aug 2023 |
Abstract
Misfolding and aggregation of transthyretin (TTR) cause several amyloid diseases. Besides being an amyloidogenic protein, TTR has an affinity for bicyclic small-molecule ligands in its thyroxine (T4) binding site. One class of TTR ligands are trans-stilbenes. The trans-stilbene scaffold is also widely applied for amyloid fibril-specific ligands used as fluorescence probes and as positron emission tomography tracers for amyloid detection and diagnosis of amyloidosis. We have shown that native tetrameric TTR binds to amyloid ligands based on the trans-stilbene scaffold providing a platform for the determination of high-resolution structures of these important molecules bound to protein. In this study, we provide spectroscopic evidence of binding and X-ray crystallographic structure data on tetrameric TTR complex with the fluorescent salicylic acid-based pyrene amyloid ligand (Py1SA), an analogue of the Congo red analogue X-34. The ambiguous electron density from the X-ray diffraction, however, did not permit Py1SA placement with enough confidence likely due to partial ligand occupancy. Instead, the preferred orientation of the Py1SA ligand in the binding pocket was determined by molecular dynamics and umbrella sampling approaches. We find a distinct preference for the binding modes with the salicylic acid group pointing into the pocket and the pyrene moiety outward to the opening of the T4 binding site. Our work provides insight into TTR binding mode preference for trans-stilbene salicylic acid derivatives as well as a framework for determining structures of TTR-ligand complexes.
ASJC Scopus subject areas
- Materials Science(all)
- Materials Chemistry
- Materials Science(all)
- Surfaces, Coatings and Films
- Chemistry(all)
- Physical and Theoretical Chemistry
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In: The Journal of Physical Chemistry Part B: Biophysics, Biomaterials, Liquids, Soft Matter, Vol. 127, No. 30, 03.08.2023, p. 6628–6635.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Binding of a Pyrene-based Fluorescent Amyloid Ligand to Transthyretin
T2 - A Combined Crystallographic and Molecular Dynamics Study
AU - Nguyen, Thi Minh Nghia
AU - Begum, Afshan
AU - Zhang, Jun
AU - Leira, Petter
AU - Todarwal, Yogesh
AU - Linares, Mathieu
AU - Norman, Patrick
AU - Derbyshire, Dean
AU - von Castelmur, Eleonore
AU - Lindgren, Mikael
AU - Hammarström, Per
AU - König, Carolin
N1 - The authors acknowledge funding by the German Research Foundation (DFG) through the Emmy Noether Young Group Leader Programme (CK, project KO 5423/1-1), the Swedish e-Science Research Centre (SeRC, MaL, PN), the Swedish Research Council (PN, Grant No. 2018-4343; PH, Grant No. 2019-04405), the Swedish Brain Foundation (PH, Grant No. ALZ2019-0004 and ALZ2022-0004), and Gustaf V and Drottning Victorias Stiftelse (PH). Computing resources were provided by the Swedish National Infrastructure for Computing (SNIC), and biophysical instrumentation was used at ProLinC core facility.
PY - 2023/8/3
Y1 - 2023/8/3
N2 - Misfolding and aggregation of transthyretin (TTR) cause several amyloid diseases. Besides being an amyloidogenic protein, TTR has an affinity for bicyclic small-molecule ligands in its thyroxine (T4) binding site. One class of TTR ligands are trans-stilbenes. The trans-stilbene scaffold is also widely applied for amyloid fibril-specific ligands used as fluorescence probes and as positron emission tomography tracers for amyloid detection and diagnosis of amyloidosis. We have shown that native tetrameric TTR binds to amyloid ligands based on the trans-stilbene scaffold providing a platform for the determination of high-resolution structures of these important molecules bound to protein. In this study, we provide spectroscopic evidence of binding and X-ray crystallographic structure data on tetrameric TTR complex with the fluorescent salicylic acid-based pyrene amyloid ligand (Py1SA), an analogue of the Congo red analogue X-34. The ambiguous electron density from the X-ray diffraction, however, did not permit Py1SA placement with enough confidence likely due to partial ligand occupancy. Instead, the preferred orientation of the Py1SA ligand in the binding pocket was determined by molecular dynamics and umbrella sampling approaches. We find a distinct preference for the binding modes with the salicylic acid group pointing into the pocket and the pyrene moiety outward to the opening of the T4 binding site. Our work provides insight into TTR binding mode preference for trans-stilbene salicylic acid derivatives as well as a framework for determining structures of TTR-ligand complexes.
AB - Misfolding and aggregation of transthyretin (TTR) cause several amyloid diseases. Besides being an amyloidogenic protein, TTR has an affinity for bicyclic small-molecule ligands in its thyroxine (T4) binding site. One class of TTR ligands are trans-stilbenes. The trans-stilbene scaffold is also widely applied for amyloid fibril-specific ligands used as fluorescence probes and as positron emission tomography tracers for amyloid detection and diagnosis of amyloidosis. We have shown that native tetrameric TTR binds to amyloid ligands based on the trans-stilbene scaffold providing a platform for the determination of high-resolution structures of these important molecules bound to protein. In this study, we provide spectroscopic evidence of binding and X-ray crystallographic structure data on tetrameric TTR complex with the fluorescent salicylic acid-based pyrene amyloid ligand (Py1SA), an analogue of the Congo red analogue X-34. The ambiguous electron density from the X-ray diffraction, however, did not permit Py1SA placement with enough confidence likely due to partial ligand occupancy. Instead, the preferred orientation of the Py1SA ligand in the binding pocket was determined by molecular dynamics and umbrella sampling approaches. We find a distinct preference for the binding modes with the salicylic acid group pointing into the pocket and the pyrene moiety outward to the opening of the T4 binding site. Our work provides insight into TTR binding mode preference for trans-stilbene salicylic acid derivatives as well as a framework for determining structures of TTR-ligand complexes.
UR - http://www.scopus.com/inward/record.url?scp=85166442446&partnerID=8YFLogxK
U2 - 10.1021/acs.jpcb.3c02147
DO - 10.1021/acs.jpcb.3c02147
M3 - Article
VL - 127
SP - 6628
EP - 6635
JO - The Journal of Physical Chemistry Part B: Biophysics, Biomaterials, Liquids, Soft Matter
JF - The Journal of Physical Chemistry Part B: Biophysics, Biomaterials, Liquids, Soft Matter
IS - 30
ER -