5O2D

PARP14 Macrodomain 2 with inhibitor

Summary for 5O2D

• Entry DOI: 10.2210/pdb5o2d/pdb
• Descriptor: Poly [ADP-ribose] polymerase 14, ~{N}-[2-(9~{H}-carbazol-1-yl)phenyl]methanesulfonamide (3 entities in total)
• Functional Keywords: parp, adp-ribose, structural genomics, structural genomics consortium, sgc, adp-ribose-binding-protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 21929.90

Authors

Uth, K.,Schuller, M.,Sieg, C.,Wang, J.,Krojer, T.,Knapp, S.,Riedels, K.,Bracher, F.,Edwards, A.M.,Arrowsmith, C.,Bountra, C.,Elkins, J.M.,Structural Genomics Consortium (SGC) (deposition date: 2017-05-20, release date: 2017-11-08, Last modification date: 2024-05-08)

Primary citation

Schuller, M.,Riedel, K.,Gibbs-Seymour, I.,Uth, K.,Sieg, C.,Gehring, A.P.,Ahel, I.,Bracher, F.,Kessler, B.M.,Elkins, J.M.,Knapp, S.
Discovery of a Selective Allosteric Inhibitor Targeting Macrodomain 2 of Polyadenosine-Diphosphate-Ribose Polymerase 14.
ACS Chem. Biol., 12:2866-2874, 2017

PubMed Abstract: Macrodomains are conserved protein interaction modules that can be found in all domains of life including in certain viruses. Macrodomains mediate recognition of sequence motifs harboring adenosine diphosphate ribose (ADPR) modifications, thereby regulating a variety of cellular processes. Due to their role in cancer or viral pathogenesis, macrodomains have emerged as potential therapeutic targets, but the unavailability of small molecule inhibitors has hampered target validation studies so far. Here, we describe an efficient screening strategy for identification of small molecule inhibitors that displace ADPR from macrodomains. We report the discovery and characterization of a macrodomain inhibitor, GeA-69, selectively targeting macrodomain 2 (MD2) of PARP14 with low micromolar affinity. Co-crystallization of a GeA-69 analogue with PARP14 MD2 revealed an allosteric binding mechanism explaining its selectivity over other human macrodomains. We show that GeA-69 engages PARP14 MD2 in intact cells and prevents its localization to sites of DNA damage.

PubMed: 28991428
DOI: 10.1021/acschembio.7b00445

Experimental method

X-RAY DIFFRACTION (1.6 Å)