{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:53:34Z","timestamp":1785434014231,"version":"3.56.0"},"reference-count":42,"publisher":"International Union of Crystallography (IUCr)","issue":"4","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/legalcode"},{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/legalcode"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC 111-2112-M-213-014"],"award-info":[{"award-number":["NSTC 111-2112-M-213-014"]}]},{"name":"National Science and Technology Council","award":["NSTC 113-2923-M-001-MY3"],"award-info":[{"award-number":["NSTC 113-2923-M-001-MY3"]}]},{"DOI":"10.13039\/501100001869","name":"Academia Sinica","doi-asserted-by":"publisher","award":["112DCA0100015"],"award-info":[{"award-number":["112DCA0100015"]}],"id":[{"id":"10.13039\/501100001869","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Veteran General Hospital"}],"content-domain":{"domain":["iucr.org","wiley.com","iucrj.org"],"crossmark-restriction":true},"short-container-title":["J Appl Crystallogr","J Appl Cryst"],"accepted":{"date-parts":[[2025,5,25]]},"published-print":{"date-parts":[[2025,8,1]]},"abstract":"<jats:p>\n                    Human transthyretin (TTR) is a homotetrameric protein involved in transporting thyroxine (T4) and retinol-binding protein within serum and cerebrospinal fluid. The disassociation of TTR's tetrameric structure can lead to the formation of biologically toxic TTR amyloid fibrils. Tolcapone, a small molecule currently under clinical trial, has shown potential as a TTR stabilizer and may act as an alternative to tafamidis, the conventional therapeutic agent used to prevent TTR dissociation. Using size-exclusion-chromatography-based small- and wide-angle X-ray scattering (SEC-SWAXS) complemented by nuclear magnetic resonance (NMR) spectroscopy, this study reveals the solution conformations of Apo-TTR and TTR complexed with tolcapone and tafamidis. Our results indicate that both compounds can bind similarly to the two T4 sites of TTR, leading to a small increase in the radius of gyration from 24.3 \u00b1 0.1\u2005\u00c5 (Apo-TTR) to 25.8 \u00b1 0.1\u2005\u00c5. Consequently, both compounds largely stabilize the TTR against dissociation, denaturation and oligomerization up to 8\u2005\n                    <jats:italic>M<\/jats:italic>\n                    urea, whereas Apo-TTR starts to denature at this concentration and forms larger oligomers at 8\u2005\n                    <jats:italic>M<\/jats:italic>\n                    urea. Additionally, under a reduced TTR\u2013drug mixing ratio of 1:1, which targets only one T4 site, tafamidis more effectively stabilizes the TTR tetrameric conformation at 8\u2005\n                    <jats:italic>M<\/jats:italic>\n                    urea, a difference attributed to its higher affinity for the first T4 site. These results illustrate an effective strategy for investigating protein\u2013drug interactions by examining the solution conformations of protein\u2013drug complexes under physiological conditions, providing structural hints to the design of therapeutic agents targeting TTR.\n                  <\/jats:p>","DOI":"10.1107\/s1600576725004716","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T10:21:53Z","timestamp":1750674113000},"page":"1373-1383","update-policy":"https:\/\/doi.org\/10.1107\/cm_01","source":"Crossref","is-referenced-by-count":2,"title":["Differentiating the solution structures and stability of transthyretin tetramer complexed with tolcapone and tafamidis using SEC-SWAXS and NMR"],"prefix":"10.1107","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0610-6856","authenticated-orcid":true,"given":"Orion","family":"Shih","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00k575643","id-type":"ROR","asserted-by":"publisher"}]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chen","family":"Feng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05bxb3784","id-type":"ROR","asserted-by":"publisher"}],"department":["Institute of Atomic and Molecular Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sashank","family":"Agrawal","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05bxb3784","id-type":"ROR","asserted-by":"publisher"}],"department":["Institute of Atomic and Molecular Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuei-Fen","family":"Liao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/059dkdx38","id-type":"ROR","asserted-by":"publisher"}],"department":["Department of Chemistry"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2387-3600","authenticated-orcid":true,"given":"Yi-Qi","family":"Yeh","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00k575643","id-type":"ROR","asserted-by":"publisher"}]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Je-Wei","family":"Chang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00k575643","id-type":"ROR","asserted-by":"publisher"}]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsyr-Yan","family":"Yu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05bxb3784","id-type":"ROR","asserted-by":"publisher"}],"department":["Institute of Atomic and Molecular Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2247-5061","authenticated-orcid":true,"given":"U-Ser","family":"Jeng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00k575643","id-type":"ROR","asserted-by":"publisher"}]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"329","published-online":{"date-parts":[[2025,7,8]]},"reference":[{"key":"vg5150_bb1","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1038\/s41594-024-01472-7","volume":"32","author":"Basanta","year":"2025","journal-title":"Nat. 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