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Structure of the mammalian NOS regulator dimethylarginine dimethylaminohydrolase: A basis for the design of specific inhibitors.

MPG-Autoren
http://pubman.mpdl.mpg.de/cone/persons/resource/persons117946

Frey,  Daniel
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society;

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Zitation

Frey, D., Braun, O., Briand, C., Vasak, M., & Grütter, M. G. (2006). Structure of the mammalian NOS regulator dimethylarginine dimethylaminohydrolase: A basis for the design of specific inhibitors. Structure, 14(5), 901-911. doi:10.1016/j.str.2006.03.006.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0019-9AC8-C
Zusammenfassung
Dimethylarginine dimethylaminohydrolase (DDAH) is involved in the regulation of nitric oxide synthase (NOS) by metabolizing the free endogenous arginine derivatives Nω−methyl−L−arginine (MMA) and Nω,Nω−dimethyl−L−arginine (ADMA), which are competitive inhibitors of NOS. Here, we present high−resolution crystal structures of DDAH isoform 1 (DDAH−1) isolated from bovine brain in complex with different inhibitors, including S−nitroso−L−homocysteine and Zn2+, a regulator of this mammalian enzyme. The structure of DDAH−1 consists of a propeller−like fold similar to other arginine−modifying enzymes and a flexible loop, which adopts different conformations and acts as a lid at the entrance of the active site. The orientation and interaction mode of inhibitors in the active site give insight into the regulation and the molecular mechanism of the enzyme. The presented structures provide a basis for the structure−based development of specific DDAH−1 inhibitors that might be useful in the therapeutic treatment of NOS dysfunction−related diseases