2AEB

Crystal structure of human arginase I at 1.29 A resolution and exploration of inhibition in immune response.

Summary for 2AEB

• Entry DOI: 10.2210/pdb2aeb/pdb
• Related: 1D3V 1WVA 2ZAV
• Descriptor: Arginase 1, MANGANESE (II) ION, 2(S)-AMINO-6-BORONOHEXANOIC ACID, ... (4 entities in total)
• Functional Keywords: hydrolase, binuclear manganese cluster, boronic acid inhibitor, perfectly twinned crystal, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P05089
• Total number of polymer chains: 2
• Total formula weight: 70163.51

Authors

Di Costanzo, L.,Sabio, G.,Mora, A.,Rodriguez, P.C.,Ochoa, A.C.,Centeno, F.,Christianson, D.W. (deposition date: 2005-07-21, release date: 2005-09-06, Last modification date: 2023-08-23)

Primary citation

Di Costanzo, L.,Sabio, G.,Mora, A.,Rodriguez, P.C.,Ochoa, A.C.,Centeno, F.,Christianson, D.W.
Crystal structure of human arginase I at 1.29 A resolution and exploration of inhibition in the immune response.
Proc.Natl.Acad.Sci.Usa, 102:13058-13063, 2005

PubMed Abstract: Human arginase I is a potential target for therapeutic intervention in diseases linked to compromised l-arginine homeostasis. Here, we report high-affinity binding of the reaction coordinate analogue inhibitors 2(S)-amino-6-boronohexanoic acid (ABH, Kd = 5 nM) and S-(2-boronoethyl)-l-cysteine (BEC, Kd = 270 nM) to human arginase I, and we report x-ray crystal structures of the respective enzyme-inhibitor complexes at 1.29- and 1.94-A resolution determined from crystals twinned by hemihedry. The ultrahigh-resolution structure of the human arginase I-ABH complex yields an unprecedented view of the binuclear manganese cluster and illuminates the structural basis for nanomolar affinity: bidentate inner-sphere boronate-manganese coordination interactions and fully saturated hydrogen bond networks with inhibitor alpha-amino and alpha-carboxylate groups. These interactions are therefore implicated in the stabilization of the transition state for l-arginine hydrolysis. Electron density maps also reveal that active-site residue H141 is protonated as the imidazolium cation. The location of H141 is such that it could function as a general acid to protonate the leaving amino group of l-ornithine during catalysis, and this is a revised mechanistic proposal for arginase. This work serves as a foundation for studying the structural and chemical biology of arginase I in the immune response, and we demonstrate the inhibition of arginase activity by ABH in human and murine myeloid cells.

PubMed: 16141327
DOI: 10.1073/pnas.0504027102

Experimental method

X-RAY DIFFRACTION (1.29 Å)