000168608 001__ 168608
000168608 005__ 20260211123813.0
000168608 0247_ $$2doi$$a10.1073/pnas.2519908122
000168608 0248_ $$2sideral$$a148009
000168608 037__ $$aART-2025-148009
000168608 041__ $$aeng
000168608 100__ $$aPinheiro, Francisca
000168608 245__ $$aMass spectrometry footprinting reveals how kinetic stabilizers counteract transthyretin dynamics altered by pathogenic mutations
000168608 260__ $$c2025
000168608 5060_ $$aAccess copy available to the general public$$fUnrestricted
000168608 5203_ $$aThe aggregation of transthyretin (TTR) results in life-threatening transthyretin amyloidosis. Familial forms of the disease arise from point mutations that destabilize the TTR tetramer, leading to its dissociation and/or monomer unfolding and subsequent formation of amyloid fibrils. Small molecules that kinetically stabilize the native tetramer effectively inhibit this aggregation. Although over 300 X-ray crystal structures of TTR have been determined, these data refer to a static structure and do not capture the conformational effects of mutations and ligand binding. Here, we demonstrate that hydrogen–deuterium exchange (HDX) and fast photochemical oxidation of proteins (FPOP) coupled with mass spectrometry (MS) offer critical insights into the conformational dynamics associated with TTR amyloidogenic mutations and the binding of kinetic stabilizers. The results indicate that the design of TTR binders should consider the specific conformational traits of each TTR pathogenic variant. We propose that incorporating MS-based techniques into TTR drug discovery will expedite the development of effective pathology-specific aggregation inhibitors.
000168608 536__ $$9info:eu-repo/grantAgreement/ES/AGAUR/2021 SGR00635$$9info:eu-repo/grantAgreement/ES/MICINN/AEI/PID2021-127296OB-I00$$9info:eu-repo/grantAgreement/ES/MICINN/PID2021-124602OB-I00$$9info:eu-repo/grantAgreement/ES/MICINN/PID2022-137963OB-I00
000168608 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
000168608 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000168608 700__ $$aKant, Ravi
000168608 700__ $$aChemuru, Saketh
000168608 700__ $$aVarejão, Nathalia
000168608 700__ $$0(orcid)0000-0001-5702-4538$$aVelázquez-Campoy, Adrián$$uUniversidad de Zaragoza
000168608 700__ $$aReverter, David
000168608 700__ $$aPallarès, Irantzu
000168608 700__ $$aGross, Michael L.
000168608 700__ $$aVentura, Salvador
000168608 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000168608 773__ $$g123, 1 (2025), [11 pp.]$$pProc. Natl. Acad. Sci.$$tProceedings of the National Academy of Sciences of the United States of America$$x0027-8424
000168608 8564_ $$s4032530$$uhttps://zaguan.unizar.es/record/168608/files/texto_completo.pdf$$yVersión publicada
000168608 8564_ $$s3554204$$uhttps://zaguan.unizar.es/record/168608/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000168608 909CO $$ooai:zaguan.unizar.es:168608$$particulos$$pdriver
000168608 951__ $$a2026-02-11-10:28:11
000168608 980__ $$aARTICLE