9F9K

Crystal structure of MUS81-EME1 bound by compound 15.

This is a non-PDB format compatible entry.

Summary for 9F9K

• Entry DOI: 10.2210/pdb9f9k/pdb
• Related: 9F98 9F99 9F9A
• Descriptor: Crossover junction endonuclease MUS81, Crossover junction endonuclease EME1, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: endonuclease, fragment, drug discovery, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 141273.36

Authors

Collie, G.W. (deposition date: 2024-05-07, release date: 2024-07-03, Last modification date: 2024-07-31)

Primary citation

Collie, G.W.,Borjesson, U.,Chen, Y.,Dong, Z.,Di Fruscia, P.,Gohlke, A.,Hoyle, A.,Hunt, T.A.,Jesani, M.H.,Luo, H.,Luptak, J.,Milbradt, A.G.,Narasimhan, P.,Packer, M.,Patel, S.,Qiao, J.,Storer, R.I.,Stubbs, C.J.,Tart, J.,Truman, C.,Wang, A.T.,Wheeler, M.G.,Winter-Holt, J.
Fragment-Based Discovery of Novel MUS81 Inhibitors.
Acs Med.Chem.Lett., 15:1151-1158, 2024

PubMed Abstract: MUS81 is a structure-selective endonuclease that cleaves various branched DNA structures arising from natural physiological processes such as homologous recombination and mitosis. Due to this, MUS81 is able to relieve replication stress, and its function has been reported to be critical to the survival of many cancers, particularly those with dysfunctional DNA-repair machinery. There is therefore interest in MUS81 as a cancer drug target, yet there are currently few small molecule inhibitors of this enzyme reported, and no liganded crystal structures are available to guide hit optimization. Here we report the fragment-based discovery of novel small molecule MUS81 inhibitors with sub-μM biochemical activity. These inhibitors were used to develop a novel crystal system, providing the first structural insight into the inhibition of MUS81 with small molecules.

PubMed: 39015284
DOI: 10.1021/acsmedchemlett.3c00453

Experimental method

X-RAY DIFFRACTION (2.728 Å)