LINKED KDM5A JMJ DOMAIN BOUND TO THE POTENTIAL HYDROLYSIS PRODUCT OF INHIBITOR N45 i.e. 3-((6-(4-(2-cyano-3-methylbut-2-enoyl)-1,4-diazepan-1-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid

hydrolysis product of 3-((6-(4-(2-cyano-3-methylbut-2-enoyl)-1,4-diazepan-1-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid

Structure-based Engineering of Reversible Covalent Inhibitors Against Histone Lysine Demethylase 5A

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.

Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases.

Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A.

Histone demethylase JARID1A,Jumonji/ARID domain-containing protein 1A,Retinoblastoma-binding protein 2,RBBP-2,Histone demethylase JARID1A,Jumonji/ARID domain-containing protein 1A,Retinoblastoma-binding protein 2,RBBP-2

HNMAGVGPGGYAAEFVPPPECPVFEPSWEEFTDPLSFIGRIRPLAEKTGICKIRPPKDWQPPFACEVKSFRFTPRVQRLN
ELEAMTRVRPREAFGFEQAVREYTLQSFGEMADNFKSDYFNMPVHMVPTELVEKEFWRLVSSIEEDVIVEYGADISSKDF
GSGFPVKDGRRKILPEEEEYALSGWNLNNMPVLEQSVLAHINVDISGMKVPWLYVGMCFSSFCWHIEDHWSYSINYLHWG
EPKTWYGVPSHAAEQLEEVMRELAPELFESQPDLLHQLVTIMNPNVLMEHGVPVYRTNQCAGEFVVTFPRAYHSGFNQGY
NFAEAVNFCT

1.2-1.35 M (NH4)2SO4, 0.1 M Tris-HCl (pH 8.6-9.2) 0-20% glycerol 25 mM (Na/K) dibasic/monobasic phosphate

National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)

unexpectedly, we did not observe the terminal cyano-3-methylbut moiety of compound N45 (PDB chemical component H6M) in the complex structure with KDM5A. It is unclear whether exposure to X-ray radiation influences the reactivity of the cyanoacrylate group or if other unknown chemical reactions could occur under the crystallization conditions. The inhibitor is modeled as if some hydrolysis has occurred.

DEMETHYLASE INHIBITION, OXIDOREDUCTASE-INHIBITOR complex

MAGVGPGGYAAEFVPPPECPVFEPSWEEFTDPLSFIGRIRPLAEKTGICKIRPPKDWQPPFACEVKSFRFTPRVQRLNEL
EAMTRVR

PREAFGFEQAVREYTLQSFGEMADNFKSDYFNMPVHMVPTELVEKEFWRLVSSIEEDVIVEYGADISSKDFGSGFPVKDG
RRKILPEEEEYALSGWNLNNMPVLEQSVLAHINVDISGMKVPWLYVGMCFSSFCWHIEDHWSYSINYLHWGEPKTWYGVP
SHAAEQLEEVMRELAPELFESQPDLLHQLVTIMNPNVLMEHGVPVYRTNQCAGEFVVTFPRAYHSGFNQGYNFAEAVNFC
T