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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 \u00c5 resolution. VCP-6 binds deeper in the binding channel than T4 with the 3\u2032,5\u2032-dichlorophenyl ring binding in the \u2018forward\u2019 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 N\u03b6 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.<\/jats:p>","DOI":"10.3390\/molecules27217206","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T02:47:26Z","timestamp":1666752446000},"page":"7206","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Structural Analysis of the Complex of Human Transthyretin with 3\u2032,5\u2032-Dichlorophenylanthranilic Acid at 1.5 \u00c5 Resolution"],"prefix":"10.3390","volume":"27","author":[{"given":"Vivian","family":"Cody","sequence":"first","affiliation":[{"name":"Hauptman-Woodward Medical Research Institute, Inc., 700 Ellicot St., Buffalo, NY 14203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia Q.","family":"Truong","sequence":"additional","affiliation":[{"name":"School of Science, RMIT University, Bundoora, VIC 3083, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce A.","family":"Holdsworth","sequence":"additional","affiliation":[{"name":"School of Science, RMIT University, Bundoora, VIC 3083, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica K.","family":"Holien","sequence":"additional","affiliation":[{"name":"School of Science, RMIT University, Bundoora, VIC 3083, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1708-9430","authenticated-orcid":false,"given":"Samantha J.","family":"Richardson","sequence":"additional","affiliation":[{"name":"School of Science, RMIT University, Bundoora, VIC 3083, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2366-569X","authenticated-orcid":false,"given":"David K.","family":"Chalmers","sequence":"additional","affiliation":[{"name":"Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0007-6796","authenticated-orcid":false,"given":"David J.","family":"Craik","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience and Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,25]]},"reference":[{"key":"ref_1","unstructured":"Braverman, L.E., and Utiger, R.D. 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