Figure 1.
Chemical structures of NAD+, ABT-888, AZD2281, XAV939, IWR1, and IWR2 and the binding modes of ABT-888 and XAV939 to PARP2 and TNKS2.
The nicotinamide in NAD+ and the nicotinamide-mimic moieties in ABT-888, AZD2281, and XAV939 are highlighted in red. ABT-888 and XAV939 bind to conserved serine and glycine residues of PARP2 and TNKS2 through three hydrogen bonds. These serine and glycine residues as well as the hydrogen bonds are highlighted in blue.
Figure 2.
Crystal Structure of the TNKS1/IWR2 complex.
(A) Surface representation of TNKS1 (colored in wheat) with IWR2 (colored in green) bound. XAV939 (colored in yellow) from the crystal structure of TNKS2/XAV939 is superimposed to illustrate that IWR2 binds to a different pocket other than the nicotinamide pocket. (B) Superposition of crystal structures of TNKS1/IWR2 (colored in wheat and green) and apo TNKS1 (colored in cyan), with residues Phe1188 and His1201 in sticks, to illustrate the opening of the induced pocket in TNKS1 upon IWR2 binding. IWR2 binds to TNKS1 through three highlighted hydrogen bonds. (C) The induced pocket, showing the hydrogen bond and hydrophobic interactions between IWR2 and TNKS1 residues, colored as in (A).
Figure 3.
Structure activity relationship of IWR compounds.
Figure 4.
Structure based sequence alignment of TNKS1, TNKS2, and other PARP family members.
Key residues Pro1187 (following deletion of two amino acids) and His1201 of the induced pocket in TNKS1 are highlighted, together with their equivalent residues in other PARP proteins, to illustrate the poor conservation of these amino acids.