2MUS

HADDOCK calculated model of LIN5001 bound to the HET-s amyloid

2MUS の概要

• エントリーDOI: 10.2210/pdb2mus/pdb
• 関連するPDBエントリー: 2LBU 2RNM
• NMR情報: BMRB: 11064
• 分子名称: Heterokaryon incompatibility protein s, 3''',4'-bis(carboxymethyl)-2,2':5',2'':5'',2''':5''',2''''-quinquethiophene-5,5''''-dicarboxylic acid (2 entities in total)
• 機能のキーワード: amyloid fibril, het-s(218-289), parallel beta-sheet, beta-solenoid, prion, luminescent conjugated polythiophene, protein fibril
• 由来する生物種: Podospora anserina (Pleurage anserina)
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 43955.31

構造登録者

Hermann, U.S.,Schuetz, A.K.,Shirani, H.,Saban, D.,Nuvolone, M.,Huang, D.H.,Li, B.,Ballmer, B.,Aslund, A.K.O.,Mason, J.J.,Rushing, E.,Budka, H.,Hammarstrom, P.,Bockmann, A.,Caflisch, A.,Meier, B.H.,Nilsson, P.K.R.,Hornemann, S.,Aguzzi, A. (登録日: 2014-09-16, 公開日: 2017-02-01, 最終更新日: 2024-05-01)

主引用文献

Herrmann, U.S.,Schutz, A.K.,Shirani, H.,Huang, D.,Saban, D.,Nuvolone, M.,Li, B.,Ballmer, B.,Aslund, A.K.,Mason, J.J.,Rushing, E.,Budka, H.,Nystrom, S.,Hammarstrom, P.,Bockmann, A.,Caflisch, A.,Meier, B.H.,Nilsson, K.P.,Hornemann, S.,Aguzzi, A.
Structure-based drug design identifies polythiophenes as antiprion compounds.
Sci Transl Med, 7:299ra123-299ra123, 2015

PubMed Abstract: Prions cause transmissible spongiform encephalopathies for which no treatment exists. Prions consist of PrP(Sc), a misfolded and aggregated form of the cellular prion protein (PrP(C)). We explore the antiprion properties of luminescent conjugated polythiophenes (LCPs) that bind and stabilize ordered protein aggregates. By administering a library of structurally diverse LCPs to the brains of prion-infected mice via osmotic minipumps, we found that antiprion activity required a minimum of five thiophene rings bearing regularly spaced carboxyl side groups. Solid-state nuclear magnetic resonance analyses and molecular dynamics simulations revealed that anionic side chains interacted with complementary, regularly spaced cationic amyloid residues of model prions. These findings allowed us to extract structural rules governing the interaction between LCPs and protein aggregates, which we then used to design a new set of LCPs with optimized binding. The new set of LCPs showed robust prophylactic and therapeutic potency in prion-infected mice, with the lead compound extending survival by >80% and showing activity against both mouse and hamster prions as well as efficacy upon intraperitoneal administration into mice. These results demonstrate the feasibility of targeted chemical design of compounds that may be useful for treating diseases of aberrant protein aggregation such as prion disease.

PubMed: 26246168
DOI: 10.1126/scitranslmed.aab1923

実験手法

SOLUTION NMR