Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds

Horton, John  R.; Liu, Xu; Gale, Molly; Wu, Lizhen; Shanks, John  R.; Zhang, Xing; Webber, Philip  J.; Bell, Joshua  S. K.; Kales, Stephen  C.; Mott, Bryan  T.; Rai, Ganesha; Jansen, Daniel  J.; Henderson, Mark  J.; Urban, Daniel  J.; Hall, Matthew  D.; Simeonov, Anton; Maloney, David  J.; Johns, Margaret  A.; Fu, Haian; Jadhav, Ajit; Vertino, Paula  M.; Yan, Qin; Cheng, Xiaodong

doi:10.1016/j.chembiol.2016.06.006

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds

Journal Article · Thu Jul 14 00:00:00 EDT 2016 · Cell Chemical Biology

DOI:https://doi.org/10.1016/j.chembiol.2016.06.006· OSTI ID:1324770

Horton, John R. ^[1]; Liu, Xu ^[1]; Gale, Molly ^[2]; Wu, Lizhen ^[2]; Shanks, John R. ^[1]; Zhang, Xing ^[1]; Webber, Philip J. ^[1]; Bell, Joshua S. K. ^[1]; Kales, Stephen C. ^[3]; Mott, Bryan T. ^[3]; Rai, Ganesha ^[3]; Jansen, Daniel J. ^[3]; Henderson, Mark J. ^[3]; Urban, Daniel J. ^[3]; Hall, Matthew D. ^[3]; Simeonov, Anton ^[3]; Maloney, David J. ^[3]; Johns, Margaret A. ^[1]; Fu, Haian ^[1]; Jadhav, Ajit ^[3] more »

Emory Univ., Atlanta, GA (United States)
Yale School of Medicine, New Haven, CT (United States)
National Inst. of Health (NIH), Bethesda, MD (United States). National Center for Advancing Translational Sciences

The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases removes methyl groups from methylated lysine 4 of histone H3. Accumulating evidence supports a role for KDM5 family members as oncogenic drivers. In this work, we compare the in vitro inhibitory properties and binding affinity of ten diverse compounds with all four family members, and present the crystal structures of the KDM5A-linked Jumonji domain in complex with eight of these inhibitors in the presence of Mn(II). All eight inhibitors structurally examined occupy the binding site of α-ketoglutarate, but differ in their specific binding interactions, including the number of ligands involved in metal coordination. We also observed inhibitor-induced conformational changes in KDM5A, particularly those residues involved in the binding of α-ketoglutarate, the anticipated peptide substrate, and intramolecular interactions. We discuss how particular chemical moieties contribute to inhibitor potency and suggest strategies that might be utilized in the successful design of selective and potent epigenetic inhibitors.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: American Cancer Society; Arthur and Sarah Merrill Foundation; National Cancer Institute (NCI); National Institutes of Health (NIH); National Science Foundation (NSF); USDOD; Winship Cancer Institute

OSTI ID:: 1324770

Journal Information:: Cell Chemical Biology, Journal Name: Cell Chemical Biology Journal Issue: 7 Vol. 23; ISSN 2451-9456

Publisher:: Cell Press - ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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