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Binding of a Pyrene...
Binding of a Pyrene-Based Fluorescent Amyloid Ligand to Transthyretin : A Combined Crystallographic and Molecular Dynamics Study
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- Minh, Nghia Nguyen Thi (author)
- Institute of Physical Chemistry and Electrochemistry, Leibniz University Hannover, Callinstr. 3A, Hannover, 30167, Germany
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- Begum, Afshan (author)
- Linköpings universitet,Uppsala universitet,Institutionen för cell- och molekylärbiologi,Linköping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linköping, Sweden.,Kemi,Tekniska fakulteten,Uppsala Univ, Sweden
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- Zhang, Jun (author)
- Linköpings universitet,Kemi,Tekniska fakulteten
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- Leira, Petter (author)
- Norwegian Univ Sci & Technol, Dept Phys, N-7491 Trondheim, Norway.
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- Todarwal, Yogesh (author)
- KTH,Teoretisk kemi och biologi,KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.
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- Linares, Mathieu, 1979- (author)
- Linköpings universitet,KTH,Teoretisk kemi och biologi,KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.;Linkooping Univ, Lab Organ Elect, ITN, SE-58183 Linkooping, Sweden.;Linköping Univ, Sci Visualizat Grp, ITN, SE-58183 Linköping, Sweden.,Medie- och Informationsteknik,Laboratoriet för organisk elektronik,Tekniska fakulteten
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- Norman, Patrick (author)
- KTH,Teoretisk kemi och biologi,KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.
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- Derbyshire, Dean (author)
- Linköpings universitet,Kemi,Tekniska fakulteten
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- von Castelmur, Eleonore (author)
- Linköpings universitet,Kemi,Tekniska fakulteten
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- Lindgren, Mikael (author)
- Norwegian Univ Sci & Technol, Dept Phys, N-7491 Trondheim, Norway.
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- Hammarström, Per (author)
- Linköpings universitet,Kemi,Tekniska fakulteten
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- Koenig, Carolin (author)
- Leibniz Univ Hannover, Inst Phys Chem & Electrochem, D-30167 Hannover, Germany.
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Institute of Physical Chemistry and Electrochemistry, Leibniz University Hannover, Callinstr 3A, Hannover, 30167, Germany Institutionen för cell- och molekylärbiologi (creator_code:org_t)
- American Chemical Society (ACS), 2023
- 2023
- English.
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In: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 127:30, s. 6628-6635
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Abstract
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- Misfolding and aggregation of transthyretin (TTR) causeseveralamyloid diseases. Besides being an amyloidogenic protein, TTR hasan affinity for bicyclic small-molecule ligands in its thyroxine (T4)binding site. One class of TTR ligands are trans-stilbenes. The trans-stilbenescaffold is also widely applied for amyloid fibril-specific ligandsused as fluorescence probes and as positron emission tomography tracersfor amyloid detection and diagnosis of amyloidosis. We have shownthat native tetrameric TTR binds to amyloid ligands based on the trans-stilbenescaffold providing a platform for the determination of high-resolutionstructures of these important molecules bound to protein. In thisstudy, we provide spectroscopic evidence of binding and X-ray crystallographicstructure data on tetrameric TTR complex with the fluorescent salicylicacid-based pyrene amyloid ligand (Py1SA), an analogue of the Congored analogue X-34. The ambiguous electron density from the X-ray diffraction,however, did not permit Py1SA placement with enough confidence likelydue to partial ligand occupancy. Instead, the preferred orientationof the Py1SA ligand in the binding pocket was determined by moleculardynamics and umbrella sampling approaches. We find a distinct preferencefor the binding modes with the salicylic acid group pointing intothe pocket and the pyrene moiety outward to the opening of the T4binding site. Our work provides insight into TTR binding mode preferencefor trans-stilbene salicylic acid derivatives as well as a frameworkfor determining structures of TTR-ligand complexes.
Subject headings
- NATURVETENSKAP -- Kemi -- Fysikalisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Physical Chemistry (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
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- ref (subject category)
- art (subject category)
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- By the author/editor
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Minh, Nghia Nguy ...
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Begum, Afshan
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Zhang, Jun
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Leira, Petter
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Todarwal, Yogesh
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Linares, Mathieu ...
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Norman, Patrick
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Derbyshire, Dean
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von Castelmur, E ...
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Lindgren, Mikael
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Hammarström, Per
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Koenig, Carolin
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Chemical Science ...
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and Physical Chemist ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Journal of Physi ...
- By the university
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Royal Institute of Technology
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Uppsala University
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Linköping University