4ZUO

Crystal structure of acetylpolyamine amidohydrolase from Mycoplana ramosa in complex with a hydroxamate inhibitor

Replaces:  4K6Q

Summary for 4ZUO

• Entry DOI: 10.2210/pdb4zuo/pdb
• Related: 4ZUM 4ZUN 4ZUP 4ZUQ 4ZUR
• Descriptor: Acetylpolyamine aminohydrolase, ZINC ION, POTASSIUM ION, ... (7 entities in total)
• Functional Keywords: acetylpolyamine amidohydrolase, arginase fold, enzyme-inhibitor complex, polyamine, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Mycoplana ramosa
• Total number of polymer chains: 2
• Total formula weight: 73852.11

Authors

Decroos, C.,Christianson, D.W. (deposition date: 2015-05-17, release date: 2015-07-29, Last modification date: 2023-09-27)

Primary citation

Decroos, C.,Christianson, D.W.
Design, Synthesis, and Evaluation of Polyamine Deacetylase Inhibitors, and High-Resolution Crystal Structures of Their Complexes with Acetylpolyamine Amidohydrolase.
Biochemistry, 54:4692-4703, 2015

PubMed Abstract: Polyamines are essential aliphatic polycations that bind to nucleic acids and accordingly are involved in a variety of cellular processes. Polyamine function can be regulated by acetylation and deacetylation, just as histone function can be regulated by lysine acetylation and deacetylation. Acetylpolyamine amidohydrolase (APAH) from Mycoplana ramosa is a zinc-dependent polyamine deacetylase that shares approximately 20% amino acid sequence identity with human histone deacetylases. We now report the X-ray crystal structures of APAH-inhibitor complexes in a new and superior crystal form that diffracts to very high resolution (1.1-1.4 Å). Inhibitors include previously synthesized analogues of N(8)-acetylspermidine bearing trifluoromethylketone, thiol, and hydroxamate zinc-binding groups [Decroos, C., Bowman, C. M., and Christianson, D. W. (2013) Bioorg. Med. Chem. 21, 4530], and newly synthesized hydroxamate analogues of shorter, monoacetylated diamines, the most potent of which is the hydroxamate analogue of N-acetylcadaverine (IC50 = 68 nM). The high-resolution crystal structures of APAH-inhibitor complexes provide key inferences about the inhibition and catalytic mechanism of zinc-dependent deacetylases. For example, the trifluoromethylketone analogue of N(8)-acetylspermidine binds as a tetrahedral gem-diol that mimics the tetrahedral intermediate and its flanking transition states in catalysis. Surprisingly, this compound is also a potent inhibitor of human histone deacetylase 8 with an IC50 of 260 nM. Crystal structures of APAH-inhibitor complexes are determined at the highest resolution of any currently existing zinc deacetylase structure and thus represent the most accurate reference points for understanding structure-mechanism and structure-inhibition relationships in this critically important enzyme family.

PubMed: 26200446
DOI: 10.1021/acs.biochem.5b00536

Experimental method

X-RAY DIFFRACTION (1.33 Å)