Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Kinetic Steering of Amyloid Formation and Polymorphism by Canagliflozin, a Type-2 Diabetes Drug.
Journal, issue, pages	J Am Chem Soc, Vol. 147, Issue 14, Page 11859-11878, Year 2025
Publish date	Apr 9, 2025
Authors	Alexander I P Taylor / Yong Xu / Martin Wilkinson / Pijush Chakraborty / Alice Brinkworth / Leon F Willis / Anastasia Zhuravleva / Neil A Ranson / Richard Foster / Sheena E Radford /
PubMed Abstract	Amyloid formation is involved in widespread health conditions such as Alzheimer's disease, Parkinson's disease, and type-2 diabetes. Amyloid fibrils have a similar cross-β architecture, but fibrils ...Amyloid formation is involved in widespread health conditions such as Alzheimer's disease, Parkinson's disease, and type-2 diabetes. Amyloid fibrils have a similar cross-β architecture, but fibrils formed by a single protein sequence can have diverse structures, varying with time, self-assembly conditions, and sequence modifications. Fibril structure has been proposed to be diagnostic of disease, but why different structures result under different conditions, especially in vitro, remains elusive. We previously identified a small molecule, YX-I-1, which inhibits in vitro amyloid formation by islet amyloid polypeptide (IAPP), a peptide hormone whose amyloid formation is involved in type-2 diabetes. Here, using YX-I-1 as a lead, we identified regulator-approved drugs with similar structures by chemical similarity analysis and substructure searches and monitored the effect of 24 of these potential ligands on IAPP amyloid assembly in vitro. We show that one such compound, canagliflozin (Invokana), a type-2 diabetes drug already in clinical use, can strongly delay the kinetics of IAPP amyloid formation, an activity independent of its intended mode of action [sodium-glucose linked transporter 2 (SGLT2) inhibitor] that may have important therapeutic implications. Combining analysis of amyloid self-assembly kinetics, biophysical characterization of monomer and fibril binding, and cryo-EM of the assembly products, we show that YX-I-1 and canagliflozin target IAPP early in aggregation, remodeling the energy landscape of primary nucleation and profoundly altering the resulting fibril structures. Early binding events thus imprint long-lasting effects on the amyloid structures that form.
External links	J Am Chem Soc / PubMed:39985130 / PubMed Central
Methods	EM (helical sym.)
Resolution	2.9 - 3.3 Å
Structure data	51726 9gz6 EMDB-51726, PDB-9gz6: WT-IAPP cryo-EM structure Type SS - control reaction Method: EM (helical sym.) / Resolution: 3.3 Å 51730 9gzp EMDB-51730, PDB-9gzp: WT-IAPP cryo-EM structure Type LL - control reaction Method: EM (helical sym.) / Resolution: 2.9 Å 51733 9gzs EMDB-51733, PDB-9gzs: WT-IAPP cryo-EM structure Type LLU - control reaction Method: EM (helical sym.) / Resolution: 3.1 Å 51734 9gzt EMDB-51734, PDB-9gzt: WT-IAPP cryo-EM structure Type LLUU - control reaction Method: EM (helical sym.) / Resolution: 2.9 Å 51735 9gzw EMDB-51735, PDB-9gzw: WT-IAPP cryo-EM structure Type LL, doxazosin reaction Method: EM (helical sym.) / Resolution: 2.9 Å 51736 9gzx EMDB-51736, PDB-9gzx: WT-IAPP cryo-EM structure Type LLU, doxazosin reaction Method: EM (helical sym.) / Resolution: 3.1 Å 51737 9gzy EMDB-51737, PDB-9gzy: WT-IAPP cryo-EM structure Type LLUU, doxazosin reaction Method: EM (helical sym.) / Resolution: 3.0 Å
Source	synthetic construct (others) homo sapiens (human)
Keywords	PROTEIN FIBRIL / Amyloid / IAPP / amylin / aggregation / type-2 diabetes / polymorph