5TH7

Complex of SETD8 with MS453

Summary for 5TH7

• Entry DOI: 10.2210/pdb5th7/pdb
• Descriptor: N-lysine methyltransferase KMT5A, N-(3-{[6,7-dimethoxy-2-(pyrrolidin-1-yl)quinazolin-4-yl]amino}propyl)propanamide, UNKNOWN ATOM OR ION, ... (5 entities in total)
• Functional Keywords: structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: Q9NQR1
• Total number of polymer chains: 2
• Total formula weight: 34398.76

Authors

Yu, W.,Tempel, W.,Babault, N.,Ma, A.,Butler, K.V.,Jin, J.,Arrowsmith, C.H.,Bountra, C.,Edwards, A.M.,Brown, P.J.,Structural Genomics Consortium (SGC) (deposition date: 2016-09-29, release date: 2016-11-09, Last modification date: 2024-11-20)

Primary citation

Butler, K.V.,Ma, A.,Yu, W.,Li, F.,Tempel, W.,Babault, N.,Pittella-Silva, F.,Shao, J.,Wang, J.,Luo, M.,Vedadi, M.,Brown, P.J.,Arrowsmith, C.H.,Jin, J.
Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase.
J. Med. Chem., 59:9881-9889, 2016

PubMed Abstract: Selective inhibitors of protein lysine methyltransferases, including SET domain-containing protein 8 (SETD8), are highly desired, as only a fraction of these enzymes are associated with high-quality inhibitors. From our previously discovered SETD8 inhibitor, we developed a more potent analog and solved a cocrystal structure, which is the first crystal structure of SETD8 in complex with a small-molecule inhibitor. This cocrystal structure allowed the design of a covalent inhibitor of SETD8 (MS453), which specifically modifies a cysteine residue near the inhibitor binding site, has an IC value of 804 nM, reacts with SETD8 with near-quantitative yield, and is selective for SETD8 against 28 other methyltransferases. We also solved the crystal structure of the covalent inhibitor in complex with SETD8. This work provides atomic-level perspective on the inhibition of SETD8 by small molecules and will help identify high-quality chemical probes of SETD8.

PubMed: 27804297
DOI: 10.1021/acs.jmedchem.6b01244

Experimental method

X-RAY DIFFRACTION (1.95 Å)