Anthony E. Pegg;John A. Secrist;Steven Ealick;Diane E. McCloskey; III;John A. Secrist, III;Wayne C. Guida;Shridhar Bale
发明人:
John A. Secrist, III,Steven Ealick,Shridhar Bale,Anthony E. Pegg,Diane E. McCloskey,Wayne C. Guida
申请号：
US12671121
公开号：
US08637485B2
申请日:
2008.08.01
申请国别(地区):
US
年份:
2014
代理人:
摘要：
The crystal structure of the complex of S-adenosylmethionine methyl ester with hΛdoMetDC F223A, a mutant where the stacking of the aromatic rings of F7, adenine and F223 would be eliminated. The structure of this mutant with the ester shows that the ligand still maintains a syn conformation aided by pi-pi interactions to F7, hydrogen bonds to the backbone of Glu67, and electrostatic interactions. Several series of AdoMet substrate analogues with a variety of substituents at the 8 position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. To understand these results, virtual modeling of the enzyme inhibitor complexes and the crystal structures of human AdoMetDC with 5′-deoxy-5′-[N-methyl-N-[2-(aminooxy)ethyl]amino-8-methyl]adenosine (MAOEMA) and 5′-deoxy-5′-[N-methyl-N-[4-(aminooxy)butyl]amino-8-ethyl]adenosine (MAOBEA) at the active site have been determined experimentally.
