Control of protein-protein interactions: structure-based discovery of low molecular weight inhibitors of the interactions between Pin1 WW domain and phosphopeptides.
Interactions involving phosphorylated Ser/Thr-Pro motifs in proteins play a key role in numerous regulatory processes in the cell. Here, we investigate potential ligands of the WW binding domain of Pin1 in order to inhibit protein-protein interactions between Pin1 and phosphopeptides. Our structure-based strategy implies the synthesis of analogues of the Ac-Thr(PO(3)H(2))-Pro-NH(2) dipeptide and relies on high resolution NMR spectroscopy to accurately measure the affinity constants even in the high micromolar range.
Smet
Caroline
C
CNRS-University of Lille 2 UMR 8525, Institut Pasteur de Lille, Molecular Drug Discovery, 3 rue du Professeur Laguesse, 59000 Lille, France.
Duckert
Jean-Frédéric
JF
Wieruszeski
Jean-Michel
JM
Landrieu
Isabelle
I
Buée
Luc
L
Lippens
Guy
G
Déprez
Benoît
B
D001665:Binding Sites; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D010748:Phosphopeptides / Q000737:chemistry* / Q000378:metabolism; D010750:Phosphoproteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D013329:Structure-Activity Relationship
D004151:Dipeptides; D008024:Ligands; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010748:Phosphopeptides; D010750:Phosphoproteins; D011994:Recombinant Proteins; C502984:acetyl-phosphothreonyl-prolinamide; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase