7oth

From Proteopedia

PARP15 catalytic domain in complex with OUL219

Structural highlights

7oth is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.7Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PAR15_HUMAN Transcriptional repressor. Has ADP-ribosyltransferase activity.

Publication Abstract from PubMed

The scaffold of TIQ-A, a previously known inhibitor of human poly-ADP-ribosyltransferase PARP1, was utilized to develop inhibitors against human mono-ADP-ribosyltransferases through structure-guided design and activity profiling. By supplementing the TIQ-A scaffold with small structural changes, based on a PARP10 inhibitor OUL35, selectivity changed from poly-ADP-ribosyltransferases towards mono-ADP-ribosyltransferases. Binding modes of analogs were experimentally verified by determining complex crystal structures with mono-ADP-ribosyltransferase PARP15 and with poly-ADP-ribosyltransferase TNKS2. The best analogs of the study achieved 10-20-fold selectivity towards mono-ADP-ribosyltransferases PARP10 and PARP15 while maintaining micromolar potencies. The work demonstrates a route to differentiate compound selectivity between mono- and poly-ribosyltransferases of the human ARTD family.

Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs.,Maksimainen MM, Murthy S, Sowa ST, Galera-Prat A, Rolina E, Heiskanen JP, Lehtio L Bioorg Med Chem. 2021 Nov 10;52:116511. doi: 10.1016/j.bmc.2021.116511. PMID:34801828^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Maksimainen MM, Murthy S, Sowa ST, Galera-Prat A, Rolina E, Heiskanen JP, Lehtiö L. Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs. Bioorg Med Chem. 2021 Dec 15;52:116511. PMID:34801828 doi:10.1016/j.bmc.2021.116511