3NJ4

Fluoro-neplanocin A in Human S-Adenosylhomocysteine Hydrolase

Summary for 3NJ4

• Entry DOI: 10.2210/pdb3nj4/pdb
• Descriptor: Adenosylhomocysteinase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, (4S,5S)-4-(6-amino-9H-purin-9-yl)-3-fluoro-5-hydroxy-2-(hydroxymethyl)cyclopent-2-en-1-one, ... (4 entities in total)
• Functional Keywords: s-adenosylhomocystein, hydrolase, nad
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P23526
• Total number of polymer chains: 4
• Total formula weight: 195991.52

Authors

Jeong, L.S.,Lee, K.M.,Hwang, K.Y.,Choi, S.,Heo, Y.S. (deposition date: 2010-06-17, release date: 2011-05-04, Last modification date: 2024-03-20)

Primary citation

Lee, K.M.,Choi, W.J.,Lee, Y.,Lee, H.J.,Zhao, L.X.,Lee, H.W.,Park, J.G.,Kim, H.O.,Hwang, K.Y.,Heo, Y.S.,Choi, S.,Jeong, L.S.
X-ray crystal structure and binding mode analysis of human S-adenosylhomocysteine hydrolase complexed with novel mechanism-based inhibitors, haloneplanocin A analogues.
J.Med.Chem., 54:930-938, 2011

PubMed Abstract: The X-ray crystal structure of human S-adenosylhomocysteine (AdoHcy) hydrolase was first determined as a tetrameric form bound with the novel mechanism-based inhibitor fluoroneplanocin A (4b). The crystallized enzyme complex showed the closed conformation and turned out to be the intermediate of mechanism-based inhibition. It confirmed that the cofactor depletion by 3'-oxidation of fluoroneplanocin A contributes to the enzyme inhibition along with the irreversible covalent modification of AdoHcy hydrolase. In addition, a series of haloneplanocin A analogues (4b-e and 5b-e) were designed and synthesized to characterize the binding role and reactivity of the halogen substituents and the 4'-CH(2)OH group. The biological evaluation and molecular modeling studies identified the key pharmacophores and structural requirements for the inhibitor binding of AdoHcy hydrolase. The inhibitory activity was decreased as the size of the halogen atom increased and/or if the 4'-CH(2)OH group was absent. These results could be utilized to design new therapeutic agents operating via AdoHcy hydrolase inhibition.

PubMed: 21226494
DOI: 10.1021/jm1010836

Experimental method

X-RAY DIFFRACTION (2.5 Å)