5W4B

The crystal structure of human S-adenosylhomocysteine hydrolase (AHCY) bound to benzothiazole inhibitor

Summary for 5W4B

• Entry DOI: 10.2210/pdb5w4b/pdb
• Related: 5W49
• Descriptor: Adenosylhomocysteinase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 4-[(2,5-dioxo-2,5-dihydro-1H-imidazol-1-yl)methyl]-N-[2-(morpholin-4-yl)-1,3-benzothiazol-6-yl]benzamide, ... (5 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P23526
• Total number of polymer chains: 6
• Total formula weight: 291377.10

Authors

Dougan, D.R.,Lawson, J.D.,Lane, W. (deposition date: 2017-06-09, release date: 2017-06-28, Last modification date: 2024-03-13)

Primary citation

Uchiyama, N.,Dougan, D.R.,Lawson, J.D.,Kimura, H.,Matsumoto, S.I.,Tanaka, Y.,Kawamoto, T.
Identification of AHCY inhibitors using novel high-throughput mass spectrometry.
Biochem. Biophys. Res. Commun., 491:1-7, 2017

PubMed Abstract: S-adenosylhomocysteine hydrolase (AHCY) catalyzes the reversible hydrolysis of S-adenosylhomocysteine (SAH) to adenosine and l-homocysteine. This enzyme is frequently overexpressed in many tumor types and is considered to be a validated anti-tumor target. In order to enable the development of small molecule AHCY inhibitors as targeted cancer therapeutics we developed an assay based on a RapidFire high-throughput mass spectrometry detection system, which allows the direct measurement of AHCY enzymatic activity. This technique avoids many of the problems associate with the previously reported method of using a thiol-reactive fluorescence probes to measure AHCY activity. Screening of a ∼500,000 compound library using this technique identified multiple SAH competitive hits. Co-crystal structures of the hit compounds complexed with AHCY were obtained showing that the compounds indeed bind in the SAH site of the enzyme. In addition, some hit compounds increased the SAH levels in HCT116 cells and showed growth inhibition. These compounds could be promising starting points for the optimization of cancer treatments.

PubMed: 28533090
DOI: 10.1016/j.bbrc.2017.05.107

Experimental method

X-RAY DIFFRACTION (2.65 Å)