1HQ5

CRYSTAL STRUCTURE OF THE BINUCLEAR MANGANESE METALLOENZYME ARGINASE COMPLEXED WITH S-(2-BORONOETHYL)-L-CYSTEINE, AN L-ARGININE ANALOGUE

1HQ5 の概要

• エントリーDOI: 10.2210/pdb1hq5/pdb
• 関連するPDBエントリー: 1D3V 1RLA
• 分子名称: ARGINASE 1, MANGANESE (II) ION, S-2-(BORONOETHYL)-L-CYSTEINE, ... (4 entities in total)
• 機能のキーワード: binuclear manganese cluster, boronic acid inhibitor, perfectly twinned crystal, hydrolase
• 由来する生物種: Rattus norvegicus (Norway rat)
• 細胞内の位置: Cytoplasm : P07824
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70678.02

構造登録者

Kim, N.N.,Cox, J.D.,Baggio, R.F.,Emig, F.A.,Mistry, S.K.,Harper, S.L.,Speicher, D.W.,Morris Jr., S.M.,Ash, D.E.,Traish, A.,Christianson, D.W. (登録日: 2000-12-14, 公開日: 2001-04-04, 最終更新日: 2024-02-07)

主引用文献

Kim, N.N.,Cox, J.D.,Baggio, R.F.,Emig, F.A.,Mistry, S.K.,Harper, S.L.,Speicher, D.W.,Morris Jr., S.M.,Ash, D.E.,Traish, A.,Christianson, D.W.
Probing erectile function: S-(2-boronoethyl)-L-cysteine binds to arginase as a transition state analogue and enhances smooth muscle relaxation in human penile corpus cavernosum.
Biochemistry, 40:2678-2688, 2001

PubMed Abstract: The boronic acid-based arginine analogue S-(2-boronoethyl)-L-cysteine (BEC) has been synthesized and assayed as a slow-binding competitive inhibitor of the binuclear manganese metalloenzyme arginase. Kinetic measurements indicate a K(I) value of 0.4-0.6 microM, which is in reasonable agreement with the dissociation constant of 2.22 microM measured by isothermal titration calorimetry. The X-ray crystal structure of the arginase-BEC complex has been determined at 2.3 A resolution from crystals perfectly twinned by hemihedry. The structure of the complex reveals that the boronic acid moiety undergoes nucleophilic attack by metal-bridging hydroxide ion to yield a tetrahedral boronate anion that bridges the binuclear manganese cluster, thereby mimicking the tetrahedral intermediate (and its flanking transition states) in the arginine hydrolysis reaction. Accordingly, the binding mode of BEC is consistent with the structure-based mechanism proposed for arginase as outlined in Cox et al. [Cox, J. D., Cama, E., Colleluori D. M., Pethe, S., Boucher, J. S., Mansuy, D., Ash, D. E., and Christianson, D. W. (2001) Biochemistry 40, 2689-2701.]. Since BEC does not inhibit nitric oxide synthase, BEC serves as a valuable reagent to probe the physiological relationship between arginase and nitric oxide (NO) synthase in regulating the NO-dependent smooth muscle relaxation in human penile corpus cavernosum tissue that is required for erection. Consequently, we demonstrate that arginase is present in human penile corpus cavernosum tissue, and that the arginase inhibitor BEC causes significant enhancement of NO-dependent smooth muscle relaxation in this tissue. Therefore, human penile arginase is a potential target for the treatment of sexual dysfunction in the male.

PubMed: 11258879
DOI: 10.1021/bi002317h

実験手法

X-RAY DIFFRACTION (2.3 Å)