TY - JOUR
T1 - Chemoproteomic Study Uncovers HemK2/KMT9 As a New Target for NTMT1 Bisubstrate Inhibitors
AU - Chen, Dongxing
AU - Meng, Ying
AU - Yu, Dan
AU - Noinaj, Nicholas
AU - Cheng, Xiaodong
AU - Huang, Rong
N1 - Funding Information:
The authors acknowledge the support from NIH grants R01GM117275 (R.H.), 1R01GM127896 (N.N.), 1R01AI127793 (N.N.), R35GM134744 (X.C.), and P30 CA023168 (Purdue University Center for Cancer Research). X.C., a CPRIT Scholar in Cancer Research, thanks the support of Cancer Prevention and Research Institute of Texas (RR160029). GM/CA@APS beamline has been funded in whole or in part with federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006).
Funding Information:
This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. We also thank support from the Department of Medicinal Chemistry and Molecular Pharmacology (R.H.) and the Department of Biological Sciences (N.N.) at Purdue University. We thank C. Woodcock for previous invovlment in purification of the human HemK2–Trm112 complex. We thank the Laboratory for Biological Mass Spectrometry at Indiana University for LC-MS/MS analysis and raw data process.
Publisher Copyright:
©
PY - 2021/7/16
Y1 - 2021/7/16
N2 - Understanding the selectivity of methyltransferase inhibitors is important to dissecting the functions of each methyltransferase target. From this perspective, we report a chemoproteomic study to profile the selectivity of a potent protein N-terminal methyltransferase 1 (NTMT1) bisubstrate inhibitor NAH-C3-GPKK (Ki, app = 7 ± 1 nM) in endogenous proteomes. First, we describe the rational design, synthesis, and biochemical characterization of a new chemical probe 6, a biotinylated analogue of NAH-C3-GPKK. Next, we systematically analyze protein networks that may selectively interact with the biotinylated probe 6 in concert with the competitor NAH-C3-GPKK. Besides NTMT1, the designated NTMT1 bisubstrate inhibitor NAH-C3-GPKK was found to also potently inhibit a methyltransferase complex HemK2-Trm112 (also known as KMT9-Trm112), highlighting the importance of systematic selectivity profiling. Furthermore, this is the first potent inhibitor for HemK2/KMT9 reported until now. Thus, our studies lay the foundation for future efforts to develop selective inhibitors for either methyltransferase.
AB - Understanding the selectivity of methyltransferase inhibitors is important to dissecting the functions of each methyltransferase target. From this perspective, we report a chemoproteomic study to profile the selectivity of a potent protein N-terminal methyltransferase 1 (NTMT1) bisubstrate inhibitor NAH-C3-GPKK (Ki, app = 7 ± 1 nM) in endogenous proteomes. First, we describe the rational design, synthesis, and biochemical characterization of a new chemical probe 6, a biotinylated analogue of NAH-C3-GPKK. Next, we systematically analyze protein networks that may selectively interact with the biotinylated probe 6 in concert with the competitor NAH-C3-GPKK. Besides NTMT1, the designated NTMT1 bisubstrate inhibitor NAH-C3-GPKK was found to also potently inhibit a methyltransferase complex HemK2-Trm112 (also known as KMT9-Trm112), highlighting the importance of systematic selectivity profiling. Furthermore, this is the first potent inhibitor for HemK2/KMT9 reported until now. Thus, our studies lay the foundation for future efforts to develop selective inhibitors for either methyltransferase.
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U2 - 10.1021/acschembio.1c00279
DO - 10.1021/acschembio.1c00279
M3 - Article
C2 - 34192867
AN - SCOPUS:85110993384
SN - 1554-8929
VL - 16
SP - 1234
EP - 1242
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 7
ER -