7OSS

PARP15 catalytic domain in complex with OUL194

Summary for 7OSS

• Entry DOI: 10.2210/pdb7oss/pdb
• Related: 7OQQ 7OSP
• Descriptor: Protein mono-ADP-ribosyltransferase PARP15, 8-phenylmethoxy-4~{H}-thieno[2,3-c]isoquinolin-5-one, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, adp-ribosyl-transferase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 51264.42

Authors

Maksimainen, M.M.,Lehtio, L. (deposition date: 2021-06-09, release date: 2021-12-08, Last modification date: 2024-01-31)

Primary citation

Maksimainen, M.M.,Murthy, S.,Sowa, S.T.,Galera-Prat, A.,Rolina, E.,Heiskanen, J.P.,Lehtio, L.
Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs.
Bioorg.Med.Chem., 52:116511-116511, 2021

PubMed Abstract: 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.

PubMed: 34801828
DOI: 10.1016/j.bmc.2021.116511

Experimental method

X-RAY DIFFRACTION (1.5 Å)