PDBsum entry 1d3v

Hydrolase

PDB id: 1d3v

Contents

Protein chains

308 a.a. *

Ligands

ABH ×2

Metals

_MN ×4

Waters ×297

* Residue conservation analysis

PDB id:

1d3v

Name:

Hydrolase

Title:

Crystal structure of the binuclear manganese metalloenzyme arginase complexed with 2(s)-amino-6-boronohexanoic acid, an l-arginine analog

Structure:

Protein (arginase). Chain: a, b. Engineered: yes

Source:

Rattus norvegicus. Norway rat. Organism_taxid: 10116. Organ: liver. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Trimer (from PDB file)

Resolution:

1.70Å R-factor: 0.157 R-free: 0.179

Authors:

J.D.Cox,N.N.Kim,A.M.Traish,D.W.Christianson

Key ref:

J.D.Cox et al. (1999). Arginase-boronic acid complex highlights a physiological role in erectile function. Nat Struct Biol, 6, 1043-1047. PubMed id: 10542097 DOI: 10.1038/14929

Date:

01-Oct-99 Release date: 17-Nov-99

Protein chains

P07824  (ARGI1_RAT) -  Arginase-1 from Rattus norvegicus

Seq: 323 a.a.

Struc: 308 a.a.

Enzyme reactions

• Enzyme class: E.C.3.5.3.1 - arginase.
• Pathway: Urea Cycle and Arginine Biosynthesis
• Reaction: L-arginine + H2O = urea + L-ornithine

L-arginine + H2O = urea (Bound ligand (Het Group name = ABH) matches with 57.14% similarity) + L-ornithine

• Cofactor: Mn(2+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1038/14929

Nat Struct Biol 6:1043-1047 (1999)

PubMed id: 10542097

Arginase-boronic acid complex highlights a physiological role in erectile function.

J.D.Cox, N.N.Kim, A.M.Traish, D.W.Christianson.

ABSTRACT

The crystal structure of the complex between the binuclear manganese metalloenzyme arginase and the boronic acid analog of L-arginine, 2(S)-amino-6-boronohexanoic acid (ABH), has been determined at 1.7 A resolution from a crystal perfectly twinned by hemihedry. ABH binds as the tetrahedral boronate anion, with one hydroxyl oxygen symmetrically bridging the binuclear manganese cluster and a second hydroxyl oxygen coordinating to Mn2+A. This binding mode mimics the transition state of a metal-activated hydroxide mechanism. This transition state structure differs from that occurring in NO biosynthesis, thereby explaining why ABH does not inhibit NO synthase. We also show that arginase activity is present in the penis. Accordingly, the tight binding and specificity of ABH allows us to probe the physiological role of arginase in modulating the NO-dependent smooth muscle relaxation required for erection. Strikingly, ABH causes significant enhancement of nonadrenergic, noncholinergic nerve-mediated relaxation of penile corpus cavernosum smooth muscle, suggesting that arginase inhibition sustains L-arginine concentrations for NO synthase activity. Therefore, human penile arginase is a potential target for therapeutic intervention in the treatment of erectile dysfunction.

Selected figure(s)

Figure 1.
Figure 1. L-Arginine catabolism. a, Structure-based mechanism of arginase^16, in which metal-activated hydroxide ion attacks the substrate guanidinium group to form a tetrahedral intermediate (for clarity, only the side chain atoms of substrate L-arginine are shown). Proton transfer mediated by Asp 128 facilitates collapse of this intermediate to form products L-ornithine and urea. Following product dissociation, a nucleophilic metal-bridging hydroxide ion is regenerated from a metal-bridging water by proton transfer to bulk solvent. His 141 may function as a proton shuttle as indicated. b, Reciprocal coordination of arginase and nitric oxide pathways; note that N^ -hydroxy-L-arginine is an intermediate in the NO synthase reaction. c, The arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) is an isostere of L-arginine.

Figure 2.
Figure 2. Arginase−ABH complex. a, Omit electron density map of ABH in the arginase active site averaged over the two monomers in the asymmetric unit and averaged over the two twin domains A and B as described in the text. The map is contoured at 7.7 and selected active site residues are indicated. Atoms are color-coded as follows: C = yellow, O = red, N = blue, B = pale green; water molecules appear as red spheres. This figure was generated with BOBSCRIPT and Raster3D^34, ^35. b, Summary of arginase−ABH interactions; manganese coordination interactions are designated by green dashed lines, and hydrogen bonds are indicated by black dashed lines. c, Stabilization of the tetrahedral intermediate (and flanking transition states) in the arginase mechanism based on the binding mode of ABH.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (1999, 6, 1043-1047) copyright 1999.

Figures were selected by an automated process.