6CEN

Crystal Structure of WHSC1L1 in Complex with Inhibitor PEP21

Summary for 6CEN

• Entry DOI: 10.2210/pdb6cen/pdb
• Descriptor: Histone-lysine N-methyltransferase NSD3, ACE-GLY-VAL-NLE-ARG-ILE-NH2, S-ADENOSYLMETHIONINE, ... (5 entities in total)
• Functional Keywords: histone-lysine n-methyltransferase nsd3, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : Q9BZ95
• Total number of polymer chains: 2
• Total formula weight: 27112.05

Authors

Boriack-Sjodin, P.A.,Swinger, K.,Farrow, N.A. (deposition date: 2018-02-12, release date: 2018-05-09, Last modification date: 2024-10-16)

Primary citation

Morrison, M.J.,Boriack-Sjodin, P.A.,Swinger, K.K.,Wigle, T.J.,Sadalge, D.,Kuntz, K.W.,Scott, M.P.,Janzen, W.P.,Chesworth, R.,Duncan, K.W.,Harvey, D.M.,Lampe, J.W.,Mitchell, L.H.,Copeland, R.A.
Identification of a peptide inhibitor for the histone methyltransferase WHSC1.
PLoS ONE, 13:e0197082-e0197082, 2018

PubMed Abstract: WHSC1 is a histone methyltransferase that is responsible for mono- and dimethylation of lysine 36 on histone H3 and has been implicated as a driver in a variety of hematological and solid tumors. Currently, there is a complete lack of validated chemical matter for this important drug discovery target. Herein we report on the first fully validated WHSC1 inhibitor, PTD2, a norleucine-containing peptide derived from the histone H4 sequence. This peptide exhibits micromolar affinity towards WHSC1 in biochemical and biophysical assays. Furthermore, a crystal structure was solved with the peptide in complex with SAM and the SET domain of WHSC1L1. This inhibitor is an important first step in creating potent, selective WHSC1 tool compounds for the purposes of understanding the complex biology in relation to human disease.

PubMed: 29742153
DOI: 10.1371/journal.pone.0197082

Experimental method

X-RAY DIFFRACTION (1.61 Å)