2MUS

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

Summary for 2MUS

• Entry DOI: 10.2210/pdb2mus/pdb
• Related: 2LBU 2RNM
• NMR Information: BMRB: 11064
• Descriptor: 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)
• Functional Keywords: amyloid fibril, het-s(218-289), parallel beta-sheet, beta-solenoid, prion, luminescent conjugated polythiophene, protein fibril
• Biological source: Podospora anserina (Pleurage anserina)
• Total number of polymer chains: 5
• Total formula weight: 43955.31

Authors

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. (deposition date: 2014-09-16, release date: 2017-02-01, Last modification date: 2024-05-01)

Primary citation

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

Experimental method

SOLUTION NMR