Nature Structural Biology
8, 679 - 683 (2001)
doi:10.1038/90387
There is a Correction (September 2001) associated with this Letter.
Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolaseJudith Murray-Rust1, 2, James Leiper3, Mark McAlister4, John Phelan4, Sarah Tilley1, Jo Santa Maria3, Patrick Vallance3
& Neil McDonald1, 21
School of Crystallography, Birkbeck, Malet Street, London WC1E 7HX, UK. 2
Structural Biology Laboratory, ICRF, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. 3
Centre for Clinical Pharmacology, University College London, 5 University Street, London WC1E 6JJ, UK. 4
Bloomsbury Centre for Structural Biology, Birkbeck, Malet street>, London WC1E 7HX, UK.
Correspondence should be addressed to Neil McDonald n.mcdonald@mail.cryst.bbk.ac.ukNitric oxide synthase is inhibited by asymmetric NG-methylated derivatives of arginine whose cellular levels are controlled in part by dimethylarginine dimethylaminohydrolase (DDAH, EC 3.5.3.18). Levels of asymmetric NG,NG-dimethylarginine (ADMA) are known to correlate with certain disease states. Here, the first structure of a DDAH shows an unexpected similarity to arginine:glycine amidinotransferase (EC 2.1.4.1) and arginine deiminase (EC 3.5.3.6), thus defining a superfamily of arginine-modifying enzymes. The identification of a Cys-His-Glu catalytic triad and the structures of a Cys to Ser point mutant bound to both substrate and product suggest a reaction mechanism. Comparison of the ADMA−DDAH and arginine−amidinotransferase complexes reveals a dramatic rotation of the substrate that effectively maintains the orientation of the scissile bond of the substrate with respect to the catalytic residues. The DDAH structure will form a basis for the rational design of selective inhibitors, which are of potential use in modulating NO synthase activity in pathological settings.
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