Structural Analysis of the Complex of Human Transthyretin with 3′,5′-Dichlorophenylanthranilic Acid at 1.5 Å Resolution

Structural Analysis of the Complex of Human Transthyretin with 3′,5′-Dichlorophenylanthranilic Acid at 1.5 Å Resolution

Human transthyretin (hTTR) can form amyloid deposits that accumulate in nerves and organs, disrupting cellular function. Molecules such as tafamidis that bind to and stabilize the TTR tetramer can reduce such amyloid formation. Here, we studied the interaction of VCP-6 (2-((3,5-dichlorophenyl)amino)...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Vol. 27; no. 21; p. 7206
Main Authors: Cody, Vivian, Truong, Jia Q, Holdsworth, Bruce A, Holien, Jessica K, Richardson, Samantha J, Chalmers, David K, Craik, David J
Format: Journal Article
Language:English
Published: Basel MDPI AG 25-10-2022
MDPI
Subjects:
Affinity
Amyloid
Amyloidosis
Analysis
Benzoic acid
binding affinity
Binding sites
Chlorine
Competition
Conformation
Crystal structure
Crystallography
Gene mutations
halogen bonding
Hormones
human transthyretin
Hydrogen bonds
Iodine
Ligands
molecular structure
Nerves
Structural analysis
Thyroid
Thyroid gland
Thyroxine
Transthyretin
TTR
X-ray crystallography
Australia
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Summary:Human transthyretin (hTTR) can form amyloid deposits that accumulate in nerves and organs, disrupting cellular function. Molecules such as tafamidis that bind to and stabilize the TTR tetramer can reduce such amyloid formation. Here, we studied the interaction of VCP-6 (2-((3,5-dichlorophenyl)amino)benzoic acid) with hTTR. VCP-6 binds to hTTR with 5 times the affinity of the cognate ligand, thyroxine (T4). The structure of the hTTR:VCP-6 complex was determined by X-ray crystallography at 1.52 Å resolution. VCP-6 binds deeper in the binding channel than T4 with the 3′,5′-dichlorophenyl ring binding in the ‘forward’ mode towards the channel centre. The dichlorophenyl ring lies along the 2-fold axis coincident with the channel centre, while the 2-carboxylatephenylamine ring of VCP-6 is symmetrically displaced from the 2-fold axis, allowing the 2-carboxylate group to form a tight intermolecular hydrogen bond with Nζ of Lys15 and an intramolecular hydrogen bond with the amine of VCP-6, stabilizing its conformation and explaining the greater affinity of VCP-6 compared to T4. This arrangement maintains optimal halogen bonding interactions in the binding sites, via chlorine atoms rather than iodine of the thyroid hormone, thereby explaining why the dichloro substitution pattern is a stronger binder than either the diiodo or dibromo analogues.
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These authors contributed equally to this work.
Current address: Structural Biology Department, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 955 Main St., Rm 5132, Buffalo, NY 14203, USA.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules27217206