8AWW

Transthyretin conjugated with a tafamidis derivative

Summary for 8AWW

• Entry DOI: 10.2210/pdb8aww/pdb
• Related: 3tct
• Descriptor: Transthyretin, ~{N}-(6-azanylhexyl)-2-[3,5-bis(chloranyl)phenyl]-1,3-benzoxazole-6-carboxamide (3 entities in total)
• Functional Keywords: ttr, tafamidis, protein-drug conjugates, drug design, cancer therapy., transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 26219.05

Authors

Cerofolini, L.,Vasa, K.,Bianconi, E.,Salobehaj, M.,Cappelli, G.,Licciardi, G.,Perez-Rafols, A.,Padilla Cortes, L.D.,Antonacci, S.,Rizzo, D.,Ravera, E.,Calderone, V.,Parigi, G.,Luchinat, C.,Macchiarulo, A.,Menichetti, S.,Fragai, M. (deposition date: 2022-08-30, release date: 2023-07-12, Last modification date: 2024-02-07)

Primary citation

Cerofolini, L.,Vasa, K.,Bianconi, E.,Salobehaj, M.,Cappelli, G.,Bonciani, A.,Licciardi, G.,Perez-Rafols, A.,Padilla-Cortes, L.,Antonacci, S.,Rizzo, D.,Ravera, E.,Viglianisi, C.,Calderone, V.,Parigi, G.,Luchinat, C.,Macchiarulo, A.,Menichetti, S.,Fragai, M.
Combining Solid-State NMR with Structural and Biophysical Techniques to Design Challenging Protein-Drug Conjugates.
Angew.Chem.Int.Ed.Engl., 62:e202303202-e202303202, 2023

PubMed Abstract: Several protein-drug conjugates are currently being used in cancer therapy. These conjugates rely on cytotoxic organic compounds that are covalently attached to the carrier proteins or that interact with them via non-covalent interactions. Human transthyretin (TTR), a physiological protein, has already been identified as a possible carrier protein for the delivery of cytotoxic drugs. Here we show the structure-guided development of a new stable cytotoxic molecule based on a known strong binder of TTR and a well-established anticancer drug. This example is used to demonstrate the importance of the integration of multiple biophysical and structural techniques, encompassing microscale thermophoresis, X-ray crystallography and NMR. In particular, we show that solid-state NMR has the ability to reveal effects caused by ligand binding which are more easily relatable to structural and dynamical alterations that impact the stability of macromolecular complexes.

PubMed: 37276329
DOI: 10.1002/anie.202303202

Experimental method

X-RAY DIFFRACTION (1.6 Å)