Crystal Structure of the Transthyretin–Retinoic‐Acid Complex
Abstract
Retinoids are quite insoluble and chemically unstable compounds in the aqueous medium, such that natural retinoids need to be bound to specific retinoid‐binding proteins to be protected, solubilized and transported in body fluids. All‐trans retinoic acid exhibits a relatively high affinity for thyroxine‐binding transthyretin in vitro and this protein is a good candidate for the transport of retinoic acid administered as pharmacological or antitumor agent. To define structural features essential for the recognition by transthyretin of a ligand which is structurally unrelated to thyroxine, we have cocrystallized human transthyretin with retinoic acid and determined its structure at 0.18‐nm resolution. The retinoid fits into the two chemically identical thyroxine‐binding sites, which are located in the central channel that runs through the tetrameric transthyretin. The cyclohexene ring of the bound retinoid is innermost, occupying the same position of the phenolic ring of the bound 3,3′‐diiodo‐l‐thyronine, whereas the carboxylate group, like the same group of the thyroid hormone, participates in an ionic interaction with the Lys15 side chain at the entrance of the channel. Despite the fact that transthyretin was cocrystallized with all‐trans‐retinoic acid, the isoprene chain of the bound retinoid has been found in a non‐extended conformation. This feature, that allows the carboxylate to orient in a manner suitable for ion‐pair association with the Lys15 side chain, is attributable to the conversion of all‐trans‐retinoic acid into cis‐misomers or folded conformers. It is concluded that the presence, in an essentially hydrophobic molecular core of the appropriate size, of a negatively charged group at the correct position is a crucial requirement for ligand‐transthyretin recognition. Whereas the binding of the ligand has no remarkable consequences for the protein structure, all‐trans‐retinoic acid undergoes structural changes such as to interact favorably with residues present in the thyroxine‐binding sites, resembling roughly the natural ligand.
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RA delivery systems have been prepared by complexation of RA with proteins or cationic polymers, by physical encapsulation in polymeric or inorganic nanoparticles, microparticles, micelles, liposomes, or films, by covalent attachment of RA to a carrier, or by immobilization of RA on surfaces of nanoparticles.
“Several strategies have been used to prepare RA delivery systems: namely, by complexation of RA with proteins (e.g., transthyretin)42 or cationic polymers (e.g., poly(ethyleneimine) (PEI))43,44, by physical encapsulation in polymeric25,44 or inorganic45 nanoparticles, microparticles46, micelles47,48, liposomes49, or films43, by covalent attachment of RA to a carrier50, or by immobilization of RA”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [42]
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- Authors
- Zanotti, G., D'acunto, M. R., Malpeli, G., Folli, C., & Berni, R.
- Affiliations
- University of Padua (IT)
- University of Parma (IT)
- Corresponding author
- Zanotti, Giuseppe
- Venue
- European Journal of Biochemistry
- Publisher
- Wiley
- Published
- 1995-12
- Volume
- 234
- Issue
- 2
- Pages
- 563-569
- ISSN
- 0014-2956 (ISSN-L)
- 1432-1033
- OpenAlex
- W2079854515
- Cited by
- 40
- References
- 32
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 2 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 1 · 2015: 1 · 2014: 1 · 2013: 1 · 2012: 3
- FWCI
- 0.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- prealbumin, all-trans retinoic acid, retinoid-binding proteins, thyroxine binding site, ligand binding, protein-ligand complex, tetrameric protein structure, retinoid transport, co-crystallization
- MeSH terms
- Binding Sites, Crystallization, Humans, Ligands, Prealbumin, Protein Binding, Thyroxine, Tretinoin
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