1HQ5

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

Summary for 1HQ5

• Entry DOI: 10.2210/pdb1hq5/pdb
• Related: 1D3V 1RLA
• Descriptor: ARGINASE 1, MANGANESE (II) ION, S-2-(BORONOETHYL)-L-CYSTEINE, ... (4 entities in total)
• Functional Keywords: binuclear manganese cluster, boronic acid inhibitor, perfectly twinned crystal, hydrolase
• Biological source: Rattus norvegicus (Norway rat)
• Cellular location: Cytoplasm : P07824
• Total number of polymer chains: 2
• Total formula weight: 70678.02

Authors

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. (deposition date: 2000-12-14, release date: 2001-04-04, Last modification date: 2024-02-07)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.3 Å)