5T5G: human SETD8 in complex with MS2177

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 IC50 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.
PDB ID: 5T5GDownload
MMDB ID: 143621
PDB Deposition Date: 2016/8/30
Updated in MMDB: 2017/12
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 5T5G: dimeric; determined by software (PISA)
Molecular Components in 5T5G
Label Count Molecule
Proteins (2 molecules)
N-lysine Methyltransferase Kmt5a(Gene symbol: KMT5A)
Molecule annotation
Chemicals (14 molecules)
Molecule information is not avaliable.
* Click molecule labels to explore molecular sequence information.

Citing MMDB