Antimalarial drug quinacrine binds to C-terminal helix of cellular prion protein.
Using NMR spectroscopy we show that the cellular prion protein constitutes a target for binding of various acridine and phenothiazine derivatives. We unambiguously map the quinacrine binding site of recombinant human prion protein to residues Tyr225, Tyr226, and Gln227 of helix alpha3, which is located near the "protein X" epitope. The millimolar dissociation constant of the complex suggests that in vivo inhibition of prion propagation occurs after 10000-fold concentration of quinacrine within endolysosomes.
Vogtherr
Martin
M
Institut für Molekularbiologie und Biophysik, Eidgenössische Technische Hochschule Zürich, CH-8093 Zürich, Switzerland.
Grimme
Susanne
S
Elshorst
Bettina
B
Jacobs
Doris M
DM
Fiebig
Klaus
K
Griesinger
Christian
C
Zahn
Ralph
R
D000962:Antimalarials / Q000737:chemistry*; D001665:Binding Sites; D002738:Chloroquine / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry; D010640:Phenothiazines / Q000737:chemistry; D011328:Prions / Q000737:chemistry*; D017433:Protein Structure, Secondary; D011796:Quinacrine / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
D000962:Antimalarials; D010446:Peptide Fragments; D010640:Phenothiazines; D011328:Prions; D011994:Recombinant Proteins; D002738:Chloroquine; D011796:Quinacrine