3MFW

Crystal structure of human arginase I in complex with L-2-aminohistidine and sulphate

Summary for 3MFW

• Entry DOI: 10.2210/pdb3mfw/pdb
• Related: 3MFV
• Descriptor: Arginase-1, SULFATE ION, 2-amino-L-histidine, ... (5 entities in total)
• Functional Keywords: manganese coordination, 2-aminoimidazole derivative, structure based design, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P05089
• Total number of polymer chains: 2
• Total formula weight: 70311.97

Authors

Di Costanzo, L.,Christianson, D.W. (deposition date: 2010-04-04, release date: 2010-05-05, Last modification date: 2023-09-06)

Primary citation

Ilies, M.,Di Costanzo, L.,North, M.L.,Scott, J.A.,Christianson, D.W.
2-aminoimidazole amino acids as inhibitors of the binuclear manganese metalloenzyme human arginase I.
J.Med.Chem., 53:4266-4276, 2010

PubMed Abstract: Arginase, a key metalloenzyme of the urea cycle that converts L-arginine into L-ornithine and urea, is presently considered a pharmaceutical target for the management of diseases associated with aberrant l-arginine homeostasis, such as asthma, cardiovascular diseases, and erectile dysfunction. We now report the design, synthesis, and evaluation of a series of 2-aminoimidazole amino acid inhibitors in which the 2-aminoimidazole moiety serves as a guanidine mimetic. These compounds represent a new class of arginase inhibitors. The most potent inhibitor identified in this study, 2-(S)-amino-5-(2-aminoimidazol-1-yl)pentanoic acid (A1P, 10), binds to human arginase I with K(d) = 2 microM and significantly attenuates airways hyperresponsiveness in a murine model of allergic airways inflammation. These findings suggest that 2-aminoimidazole amino acids represent new leads for the development of arginase inhibitors with promising pharmacological profiles.

PubMed: 20441173
DOI: 10.1021/jm100306a

Experimental method

X-RAY DIFFRACTION (1.47 Å)