Binding of TCA to the prion protein: mechanism, implication for therapy, and application as probe for complex formation of bio-macromolecules.
Tricyclic aromatic compounds (TCA) are promising candidates for treatment of transmissible spongiform encephalopathies. Direct binding to the cellular prion protein (PrP(C)) has been proposed as anti-prion active mechanism. We here show by means of NMR-spectroscopy that binding of TCA occurs with millimolar affinity to motifs consisting of two neighboring aromatic residues (Ar-Ar motif). It is independent of the secondary structure of this motif and of the side chain attached to the TCA and it is not specific to PrP(C). Because biologically inactive 9-aminoacridine (9-aa) binds with similar K(D) as anti-prion active quinacrine, direct interaction with PrP(C) as mechanism of action appears highly unlikely. However, binding of 9-aa to Ar-Ar-motifs in proteins can be used as reporter for biological macromolecule interactions, by measuring changes in T(1)-NMR relaxation times of 9-aa.
Mangels
Christian
C
Department of Biopolymers, University of Bayreuth, 95440 Bayreuth, Germany.
Frank
Andreas O
AO
Ziegler
Jan
J
Klingenstein
Ralph
R
Schweimer
Kristian
K
Willbold
Dieter
D
Korth
Carsten
C
Rösch
Paul
P
Schwarzinger
Stephan
S
D000585:Aminacrine / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D006801:Humans; D008958:Models, Molecular; D015335:Molecular Probes / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D017096:Prion Diseases / Q000628:therapy*; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D011796:Quinacrine / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use
D015335:Molecular Probes; D011328:Prions; D000585:Aminacrine; D011796:Quinacrine