4Q3R

Crystal structure of Schistosoma mansoni arginase in complex with inhibitor ABHDP

Summary for 4Q3R

• Entry DOI: 10.2210/pdb4q3r/pdb
• Related: 4Q3P 4Q3Q 4Q3S 4Q3T 4Q3U 4Q3V 4Q40 4Q41 4Q42
• Descriptor: Arginase, MANGANESE (II) ION, CESIUM ION, ... (9 entities in total)
• Functional Keywords: arginase-deacetylase fold, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Schistosoma mansoni (Blood fluke); More
• Total number of polymer chains: 4
• Total formula weight: 173583.75

Authors

Hai, Y.,Edwards, J.E.,Van Zandt, M.C.,Hoffmann, K.F.,Christianson, D.W. (deposition date: 2014-04-12, release date: 2014-07-16, Last modification date: 2023-12-06)

Primary citation

Hai, Y.,Edwards, J.E.,Van Zandt, M.C.,Hoffmann, K.F.,Christianson, D.W.
Crystal Structure of Schistosoma mansoni Arginase, a Potential Drug Target for the Treatment of Schistosomiasis.
Biochemistry, 53:4671-4684, 2014

PubMed Abstract: The X-ray crystal structure of arginase from Schistosoma mansoni (SmARG) and the structures of its complexes with several amino acid inhibitors have been determined at atomic resolution. SmARG is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea, and this enzyme is upregulated in all forms of the parasite that interact with the human host. Current hypotheses suggest that parasitic arginases could play a role in host immune evasion by depleting pools of substrate l-arginine that would otherwise be utilized for NO biosynthesis and NO-dependent processes in the immune response. Although the amino acid sequence of SmARG is only 42% identical with that of human arginase I, residues important for substrate binding and catalysis are strictly conserved. In general, classical amino acid inhibitors such as 2(S)-amino-6-boronohexanoic acid (ABH) tend to bind more weakly to SmARG than to human arginase I despite identical inhibitor binding modes in each enzyme active site. The identification of a patch on the enzyme surface capable of accommodating the additional Cα substitutent of an α,α-disubstituted amino acid inhibitor suggests that such inhibitors could exhibit higher affinity and biological activity. The structures of SmARG complexed with two different α,α-disubstituted derivatives of ABH are presented and provide a proof of concept for this approach in the enhancement of enzyme-inhibitor affinity.

PubMed: 25007099
DOI: 10.1021/bi5004519

Experimental method

X-RAY DIFFRACTION (2.169 Å)